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Bashirrohelleh MA, Bavarsad K, Khodadadi A, Shohan M, Asadirad A. Curcumin-enhanced stem cell exosomes: A novel approach to modulating neuroinflammation and improving cognitive function in a rat model of Alzheimer's disease. Eur J Pharmacol 2025; 999:177695. [PMID: 40315951 DOI: 10.1016/j.ejphar.2025.177695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 04/22/2025] [Accepted: 04/30/2025] [Indexed: 05/04/2025]
Abstract
The effect of Curcumin-enhanced stem cell exosomes on the learning and memory impairment induced by streptozotocin (STZ) and neuro-inflammation in rats was evaluated. An animal model of Alzheimer's disease (AD) was established by intracerebroventricular (ICV) injection of STZ (3 mg/kg) in male Wistar rats (250 ± 50 g). ICV STZ injections chronically reduce cerebral glucose uptake and produce other effects similar to pathological, molecular and behavioral features of AD. Numerous studies confirmed the anti-inflammatory and antioxidant properties of curcumin (a natural polyphenol) against free radicals, as well as its ability to inhibit the aggregation of proteins such as beta-amyloid and alpha-synuclein in disorders such as AD and Parkinson's disease. The use of extracellular vesicles has garnered a lot of interest in research studies because of the important roles that mesenchymal stem cell-derived exosomes play in permeability, retention, and drug delivery as well as their ability to reduce inflammatory cytokines (TNF-α, IL-1β, and IL-6). Furthermore, researches highlighted the positive effect of curcumin on neuronal differentiation of stem cells in vivo and in vitro. Since studies emphasized the ameliorating effect of curcumin-treated macrophage-exosomes on symptoms of Alzheimer's disease by inhibiting tau protein phosphorylation, we proposed that Curcumin-primed MSC exosomes may offer greater efficacy to alleviate AD compared to naïve MSC exosomes. In this study, we investigated the effect of curcumin in stimulating the anti-inflammatory potential of exosome-derived stem cells. We evaluated the effect of MSC-EXO and pre-treated MSC-EXO with curcumin (CUR-MSC-EXO) on inhibiting inflammation and memory and learning impairments. Following four intraperitoneal injections of MSC-EXO and CUR-MSC-EXO at a dosage of 30μg/body over 30 days, we found that MSC-EXO and CUR-MSC-EXO elevated anti-inflammatory cytokines (IL10, TGF-β) and reduced pro-inflammatory cytokines (IL1, TNF-α) in peripheral blood compared to the AD group. The elevated level of M2 anti-inflammatory microglia markers (Arg1, CD206) and decreased level expression of M1 pro-inflammatory markers (iNOS, CD86) indicated that the CUR-MSC-EXO effect was more significant in the polarization of microglia into the M2 phenotype in the rat hippocampus. Both treatment groups demonstrated improvements in memory and learning skills. The results of the passive avoidance learning in the rats with STZ-induced memory impairment, however, were better in the CUR-MSC-EXO. Additionally, after therapy, a decrease in degenerative neurons was seen. Therefore, using curcumin may stimulate the anti-inflammatory and neuroprotective potential of exosome-derived stem cells which could provide hope for Alzheimer's disease treatment in the future.
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Affiliation(s)
- Mohammad-Ali Bashirrohelleh
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kowsar Bavarsad
- Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Persian Gulf Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Khodadadi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Shohan
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran
| | - Ali Asadirad
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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2
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Doroszkiewicz J, Winkel I, Mroczko B. Comparative analysis of neuroinflammatory pathways in Alzheimer's disease, Parkinson's disease, and multiple sclerosis: insights into similarities and distinctions. Front Neurosci 2025; 19:1579511. [PMID: 40364858 PMCID: PMC12069400 DOI: 10.3389/fnins.2025.1579511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
Neurodegenerative diseases, contributing to the significant socioeconomic burden due to aging society, are gaining increasing interest. Despite each disease having different etiologies, neuroinflammation is believed to play a crucial role in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). In addition to the pathogenic function of inflammation in the brain there is growing evidence that immune responses are essential for neuroregeneration. This review compares and contrasts the neuroinflammatory pathways that selected neurodegenerative diseases share and have in common. In AD, tau tangles and beta-amyloid plaques cause microglia and astrocytes to become activated in an inflammatory response. Alpha-synuclein aggregation stimulate neuroinflammation in Parkinson's disease, especially in the substantia nigra. In Multiple Sclerosis an autoimmune attack on myelin is connected to inflammation via invading immune cells. Commonalities include the release of pro-inflammatory mediators like cytokines and activation of signaling pathways such as NF-κB and MAPK. Comprehending these common routes is essential for discovering early diagnostic possibilities for the diseases and possible tailored treatments. Our work underscores the potential for insights into disease mechanisms. Identifying common targets offers promise for advancing our understanding and potential future treatment approaches across these debilitating disorders.
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Affiliation(s)
- Julia Doroszkiewicz
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Izabela Winkel
- Dementia Disorders Centre, Medical University of Wroclaw, Scinawa, Poland
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland
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Xie M, Huang X, Tang Q, Yu S, Zhang K, Lu X, Zhang Y, Wang J, Zhang L, Chen L. Porphyromonas gingivalis Impairs Microglial Aβ Clearance in a Mouse Model. J Dent Res 2025; 104:408-418. [PMID: 39953680 DOI: 10.1177/00220345241294009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2025] Open
Abstract
Porphyromonas gingivalis (Pg), a keystone pathogen in chronic periodontitis, has been identified as an emerging risk factor for Alzheimer's disease (AD). Pg can promote the accumulation of amyloid β protein (Aβ), a characteristic feature of AD pathology. However, the underlying mechanism, particularly in Aβ clearance, remains poorly understood. Here, by using 3 different strains of Pg, ATCC33277, W50, and W83, we discovered that APP/PS1 mice infected with all 3 Pg strains showed decreased microglial Aβ internalization, increased Aβ deposition in the brain, and impaired cognitive function. Using in vitro experiments, we further demonstrated that all 3 Pg strains inhibited microglial Aβ clearance, where gingipains, a group of toxic proteases derived from Pg, were involved. Gingipains were shown to hydrolyze CD14, subsequently impeding the CD14-mediated Vav-Rac/Cdc42 signaling cascade, which ultimately suppressed phagocytosis. Gingipain inhibitor could effectively restore microglial Aβ clearance and diminish Aβ deposition, leading to improved cognitive function in Pg-infected APP/PS1 mice. These findings may provide new insights into the mechanism through which Pg impairs microglial Aβ clearance to aggravate AD phenotypes, suggesting that gingipain inhibitors could be potential therapeutics for treating Pg-associated AD.
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Affiliation(s)
- M Xie
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - X Huang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Q Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - S Yu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - K Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - X Lu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Y Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - J Wang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - L Zhang
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - L Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
- Lead contact
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Campomayor NB, Kim HJ, Kim M. Pro-Oxidative and Inflammatory Actions of Extracellular Hemoglobin and Heme: Molecular Events and Implications for Alzheimer's and Parkinson Disease. Biomol Ther (Seoul) 2025; 33:235-248. [PMID: 39962769 PMCID: PMC11893490 DOI: 10.4062/biomolther.2024.224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 03/01/2025] Open
Abstract
Hemoglobin (Hb) and heme, which are typically confined within red blood cells (RBCs), are essential for intravascular transport of gases and nutrients. However, these molecules acquire secondary functions upon exposure to the extracellular environment. Hb and heme generate reactive oxygen species (ROS), which are potent pro-inflammatory agents that contribute to oxidative stress and cellular damage. These events are relevant to neurodegenerative processes, where oxidative stress, irregular deposition of protein aggregates, and chronic inflammation are key pathological features. Extracellular Hb, heme, and oxidative stress derived from hemorrhagic events or RBC lysis may contribute to increased blood-brain barrier (BBB) permeability. These events allow Hb and heme to interact with neuroimmune cells and pathological protein aggregates, further amplifying pro-inflammatory signaling and the progression of Alzheimer's disease (AD) and Parkinson disease (PD). Chronic neuroinflammation, oxidative stress, and mitochondrial dysfunction lead to neuronal degeneration. Here, we sought to elucidate the pro-oxidative and inflammatory actions of extracellular Hb and heme, emphasizing their potential impact on AD and PD development.
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Affiliation(s)
- Nicole Bon Campomayor
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea
- Department of Chemistry & Life Science, Sahmyook University, Seoul 01795, Republic of Korea
| | - Hee Jin Kim
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea
| | - Mikyung Kim
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea
- Department of Chemistry & Life Science, Sahmyook University, Seoul 01795, Republic of Korea
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5
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Lv R, Liu B, Jiang Z, Zhou R, Liu X, Lu T, Bao Y, Huang C, Zou G, Zhang Z, Lu L, Yin Q. Intermittent fasting and neurodegenerative diseases: Molecular mechanisms and therapeutic potential. Metabolism 2025; 164:156104. [PMID: 39674569 DOI: 10.1016/j.metabol.2024.156104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 12/16/2024]
Abstract
Neurodegenerative disorders are straining public health worldwide. During neurodegenerative disease progression, aberrant neuronal network activity, bioenergetic impairment, adaptive neural plasticity impairment, dysregulation of neuronal Ca2+ homeostasis, oxidative stress, and immune inflammation manifest as characteristic pathological changes in the cellular milieu of the brain. There is no drug for the treatment of neurodegenerative disorders, and therefore, strategies/treatments for the prevention or treatment of neurodegenerative disorders are urgently needed. Intermittent fasting (IF) is characterized as an eating pattern that alternates between periods of fasting and eating, requiring fasting durations that vary depending on the specific protocol implemented. During IF, depletion of liver glycogen stores leads to the production of ketone bodies from fatty acids derived from adipocytes, thereby inducing an altered metabolic state accompanied by cellular and molecular adaptive responses within neural networks in the brain. At the cellular level, adaptive responses can promote the generation of synapses and neurons. At the molecular level, IF triggers the activation of associated transcription factors, thereby eliciting the expression of protective proteins. Consequently, this regulatory process governs central and peripheral metabolism, oxidative stress, inflammation, mitochondrial function, autophagy, and the gut microbiota, all of which contribute to the amelioration of neurodegenerative disorders. Emerging evidence suggests that weight regulation significantly contributes to the neuroprotective effects of IF. By alleviating obesity-related factors such as blood-brain barrier dysfunction, neuroinflammation, and β-amyloid accumulation, IF enhances metabolic flexibility and insulin sensitivity, further supporting its potential in mitigating neurodegenerative disorders. The present review summarizes animal and human studies investigating the role and underlying mechanisms of IF in physiology and pathology, with an emphasis on its therapeutic potential. Furthermore, we provide an overview of the cellular and molecular mechanisms involved in regulating brain energy metabolism through IF, highlighting its potential applications in neurodegenerative disorders. Ultimately, our findings offer novel insights into the preventive and therapeutic applications of IF for neurodegenerative disorders.
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Affiliation(s)
- Renjun Lv
- Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
| | - Bin Liu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan 250014, China
| | - Ziying Jiang
- Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing, 100053, China
| | - Runfa Zhou
- Experimental Pharmacology Mannheim, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehlstr. 13-17, Mannheim 68167, Germany
| | - Xiaoxing Liu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191 Beijing, China
| | - Tangsheng Lu
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China
| | - Yanping Bao
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China
| | - Chunxia Huang
- Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China
| | - Guichang Zou
- Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China
| | - Zongyong Zhang
- Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China.
| | - Lin Lu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191 Beijing, China; National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China; Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871 Beijing, China.
| | - Qingqing Yin
- Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
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Fu J, Wang R, He J, Liu X, Wang X, Yao J, Liu Y, Ran C, Ye Q, He Y. Pathogenesis and therapeutic applications of microglia receptors in Alzheimer's disease. Front Immunol 2025; 16:1508023. [PMID: 40028337 PMCID: PMC11867950 DOI: 10.3389/fimmu.2025.1508023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
Microglia, the resident immune cells of the central nervous system, continuously monitor the brain's microenvironment through their array of specific receptors. Once brain function is altered, microglia are recruited to specific sites to perform their immune functions, including phagocytosis of misfolded proteins, cellular debris, and apoptotic cells to maintain homeostasis. When toxic substances are overproduced, microglia are over-activated to produce large amounts of pro-inflammatory cytokines, which induce chronic inflammatory responses and lead to neurotoxicity. Additionally, microglia can also monitor and protect neuronal function through microglia-neuron crosstalk. Microglia receptors are important mediators for microglia to receive external stimuli, regulate the functional state of microglia, and transmit signals between cells. In this paper, we first review the role of microglia-expressed receptors in the pathogenesis and treatment of Alzheimer's disease; moreover, we emphasize the complexity of targeting microglia for therapeutic interventions in neurodegenerative disorders to inform the discovery of new biomarkers and the development of innovative therapeutics.
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Affiliation(s)
- Jiao Fu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - RuoXuan Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - JiHui He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - XiaoJing Liu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - XinXin Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - JuMing Yao
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
| | - Ye Liu
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - ChongZhao Ran
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - QingSong Ye
- Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan, China
- Department of Stomatology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
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Lee E, Chang Y. Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer's Disease. Cells 2025; 14:168. [PMID: 39936960 PMCID: PMC11817173 DOI: 10.3390/cells14030168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/13/2025] Open
Abstract
The recent approval of lecanemab highlights that the amyloid beta (Aβ) protein is an important pathological target in Alzheimer's disease (AD) and further emphasizes the significance of neuroinflammatory pathways in regulating Aβ accumulation. Indeed, Aβ accumulation triggers microglia activation, which are key mediators in neuroinflammation. The inflammatory responses in this process can lead to neuronal damage and functional decline. Microglia secrete proinflammatory cytokines that accelerate neuronal death and release anti-inflammatory cytokines and growth factors contributing to neuronal recovery and protection. Thus, microglia play a dual role in neurodegeneration and neuroprotection, complicating their function in AD. Therefore, elucidating the complex interactions between Aβ protein, microglia, and neuroinflammation is essential for developing new strategies for treating AD. This review investigates the receptors and pathways involved in activating microglia and aims to enhance understanding of how these processes impact neuroinflammation in AD, as well as how they can be regulated. This review also analyzed studies reported in the existing literature and ongoing clinical trials. Overall, these studies will contribute to understanding the regulatory mechanisms of neuroinflammation and developing new therapies that can slow the pathological progression of AD.
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Affiliation(s)
- Eunshil Lee
- Institute of Biomedical Engineering Research, Kyungpook National University, Daegu 41944, Republic of Korea;
| | - Yongmin Chang
- Institute of Biomedical Engineering Research, Kyungpook National University, Daegu 41944, Republic of Korea;
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Radiology, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
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Mohammad Hosseini A, Khaleghzadeh-Ahangar H, Rahimi A. The immunomodulatory effects of psychedelics in Alzheimer's disease-related dementia. Neuroscience 2025; 564:271-280. [PMID: 39603407 DOI: 10.1016/j.neuroscience.2024.11.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/03/2024] [Accepted: 11/24/2024] [Indexed: 11/29/2024]
Abstract
Dementia is an increasing disorder, and Alzheimer's disease (AD) is the cause of 60% of all dementia cases. Despite all efforts, there is no cure for stopping dementia progression. Recent studies reported potential effects of psychedelics on neuroinflammation during AD. Psychedelics by 5HT2AR activation can reduce proinflammatory cytokine levels (TNF-α, IL-6) and inhibit neuroinflammation. In addition to neuroinflammation suppression, psychedelics induce neuroplasticity by increasing Brain-derived neurotrophic factor (BDNF) levels through Sigma-1R stimulation. This review discussed the effects of psychedelics on AD from both neuroinflammatory and neuroplasticity standpoints.
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Affiliation(s)
| | - Hossein Khaleghzadeh-Ahangar
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Physiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran; Mobility Impairment Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Atena Rahimi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Pharmacology and Toxicology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
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Valiukas Z, Tangalakis K, Apostolopoulos V, Feehan J. Microglial activation states and their implications for Alzheimer's Disease. J Prev Alzheimers Dis 2025; 12:100013. [PMID: 39800461 DOI: 10.1016/j.tjpad.2024.100013] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by the accumulation of toxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein in the brain. Microglia, key immune cells of the central nervous system, play an important role in AD development and progression, primarily through their responses to Aβ and NFTs. Initially, microglia can clear Aβ, but in AD, chronic activation overwhelms protective mechanisms, leading to sustained neuroinflammation that enhances plaque toxicity, setting off a damaging cycle that affects neurons, astrocytes, cerebral vasculature, and other microglia. Current AD treatments have been largely ineffective, though emerging immunotherapies focusing on plaque removal show promise, but often overlook the role of neuroinflammation. Activated microglia display a complex range of phenotypes that can be broadly broken into pro- or anti-inflammatory states, although this dichotomy does not describe the significant overlap between states. Aβ can strongly induce inflammatory activity, triggering the production of reactive oxygen species, inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), synapse engulfment, blood-brain barrier compromise, and impaired Aβ clearance. These processes contribute to neural tissue loss, manifesting as cognitive decline such as impaired executive function and memory. Conversely, anti-inflammatory activation exerts neuroprotective effects by suppressing inflammatory pathways and releasing neurotrophic factors that aid neuron repair and protection. Induction of anti-inflammatory states may offer a dual therapeutic approach to address both neuroinflammation and plaque accumulation in AD. This approach suggests potential strategies to modulate microglial phenotypes, aiming to restore neuroprotective functions and mitigate disease progression by simultaneously targeting inflammation and plaque pathology.
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Affiliation(s)
- Zachary Valiukas
- Institute for Health and Sport, Victoria University, 70/104 Ballarat Road, Footscray VIC 3011, Australia
| | - Kathy Tangalakis
- First Year College, Victoria University, 70/104 Ballarat Road, Footscray VIC 3011, Australia
| | - Vasso Apostolopoulos
- School of Health and Biomedical Sciences, RMIT University, 220 3-5 Plenty Road, Bundoora VIC 3082, Australia.
| | - Jack Feehan
- School of Health and Biomedical Sciences, RMIT University, 220 3-5 Plenty Road, Bundoora VIC 3082, Australia.
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Han Z, Zhang L, Ma M, Keshavarzi M. Effects of MicroRNAs and Long Non-coding RNAs on Beneficial Action of Exercise on Cognition in Degenerative Diseases: A Review. Mol Neurobiol 2025; 62:485-500. [PMID: 38869810 DOI: 10.1007/s12035-024-04292-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 06/06/2024] [Indexed: 06/14/2024]
Abstract
Recent research has exposed a growing body of proof underscoring the importance of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in maintaining the physical composition of neurons and influencing cognitive functioning in both standard and atypical circumstances. Extensive research has been conducted on the possible application of miRNAs and lncRNAs as biomarkers for various diseases, with a particular focus on brain disorders, as they possess remarkable durability in cell-free surroundings and can endure repeated freezing and thawing processes. It is intriguing to note that miRNAs and lncRNAs have the ability to function through paracrine mechanisms, thereby playing a role in communication between different organs. Recent research has proposed that the improvement of cognitive abilities through physical exercise in mentally healthy individuals is a valuable method for uncovering potential connections between miRNAs, or microRNAs, and lncRNAs, and human cognitive function. The process of cross-correlating data from disease models and patients with existing data will be crucial in identifying essential miRNAs and lncRNAs, which can potentially act as biomarkers or drug targets in the treatment of cognitive disorders. By combining this method with additional research in animal models, we can determine the function of these molecules and their potential impact on therapy. This article discusses the latest research about the primary miRNAs, lncRNAs, and their exosomes that are affected by physical activity in terms of human cognitive function.
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Affiliation(s)
- Zhen Han
- Department of Physical Education, Zhejiang International Studies University, Hangzhou, 310023, Zhejiang, China
| | - Lei Zhang
- Institute of Physical Education and Sports, Capital University Of Physical Education And Sports, Beijing, 100191, China.
| | - Minhang Ma
- Department of Physical Education, Zhejiang International Studies University, Hangzhou, 310023, Zhejiang, China
| | - Maryam Keshavarzi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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11
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Kenzelmann A, Boch C, Schmidt R, Richter M, Schulz M. Exploration of Novel Biomarkers for Neurodegenerative Diseases Using Proteomic Analysis and Ligand-Binding Assays. Biomedicines 2024; 12:2794. [PMID: 39767701 PMCID: PMC11673003 DOI: 10.3390/biomedicines12122794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 11/27/2024] [Accepted: 12/03/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES Neurodegenerative diseases are a major cause of morbidity and mortality worldwide, and their public health burden continues to increase. There is an urgent need to develop reliable and sensitive biomarkers to aid the timely diagnosis, disease progression monitoring, and therapeutic development for neurodegenerative disorders. Proteomic screening strategies, including antibody microarrays, are a powerful tool for biomarker discovery, but their findings should be confirmed using quantitative assays. The current study explored the feasibility of combining an exploratory proteomic strategy and confirmatory ligand-binding assays to screen for and validate biomarker candidates for neurodegenerative disorders. METHODS It analyzed cerebrospinal fluid (CSF) and plasma samples from patients with Alzheimer's disease, Parkinson's disease, and multiple sclerosis and healthy controls using an exploratory antibody microarray and validatory ligand-binding assays. RESULTS The screening antibody microarray identified differentially expressed proteins between patients with neurodegenerative diseases and healthy controls, including cluster of differentiation 14 (CD14), osteopontin, and vascular endothelial growth factor 165b. Quantitative ligand-binding assays confirmed that CD14 levels were elevated in CSF of patients with Alzheimer's disease (p = 0.0177), whereas osteopontin levels were increased in CSF of patients with Parkinson's disease (p = 0.0346). CONCLUSIONS The current study demonstrated the potential utility of combining an exploratory proteomic approach and quantitative ligand-binding assays to identify biomarker candidates for neurodegenerative disorders. To further validate and expand these findings, large-scale analyses using well-characterized samples should be conducted.
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Affiliation(s)
- Annalena Kenzelmann
- Quantitative, Translational and ADME Sciences, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
| | - Christina Boch
- Quantitative, Translational and ADME Sciences, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
| | - Ronny Schmidt
- Sciomics GmbH, Karl-Landsteiner Str. 6, 69151 Neckargemünd, Germany
| | - Mario Richter
- Quantitative, Translational and ADME Sciences, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
| | - Michael Schulz
- Quantitative, Translational and ADME Sciences, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
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12
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Shang Y, Wang Z, Yang F, Wang W, Tang Q, Guo X, Du X, Zhang X, Hao J, Lin H. FUT8 upregulates CD36 and its core fucosylation to accelerate pericyte-myofibroblast transition through the mitochondrial-dependent apoptosis pathway during AKI-CKD. Mol Med 2024; 30:222. [PMID: 39563263 PMCID: PMC11577590 DOI: 10.1186/s10020-024-00994-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 11/08/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Activation of pericytes leads to renal interstitial fibrosis, but the regulatory mechanism of pericytes in the progression from AKI to CKD remains poorly understood. CD36 activation plays a role in the progression of CKD. However, the significance of CD36 during AKI-CKD, especially in pericyte, remains to be fully defined. METHODS GEO and DISCO database were used to analyze the expression of CD36 in pericyte during AKI-CKD; IRI to conduct AKI-CKD mouse model; Hypoxia/Reoxygenation (H/R) to induce the cell model; RT-qPCR and Western blotting to detect gene expression; IP and confocal-IF to determine the core fucosylation (CF) level of CD36. Flow cytometry (AV/PI staining) to detect the cell apoptosis and JC-1 staining to react to the change of mitochondrial membrane potential. RESULTS During AKI to CKD progression, CD36 expression in pericytes is higher and may be influenced by CF. Moreover, we confirmed the positive association of CD36 expression with pericyte-myofibroblast transition and the progression of AKI-CKD in an IRI mouse model and hypoxia/reoxygenation (H/R) pericytes. Notably, we discovered that FUT8 upregulates both CD36 expression and its CF level, contributing to the activation of the mitochondrial-dependent apoptosis signaling pathway in pericytes, ultimately leading to the progression of AKI-CKD. CONCLUSION These results further identify FUT8 and CD36 as potential targets for the treatment in the progression of AKI-CKD.
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Affiliation(s)
- Yaxi Shang
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China
| | - Ziran Wang
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China
| | - Fan Yang
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China
| | - Weidong Wang
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China
| | - Qingzhu Tang
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China
| | - Xianan Guo
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China
| | - Xiangning Du
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China
| | - Xu Zhang
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China
| | - Jiaojiao Hao
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China.
| | - Hongli Lin
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116011, PR China.
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Jiang X, Wang Y, Lin Z, Li C, Wang Q, Zhang J, Liu X, Li Z, Cui C. Polygonatum sibiricum polysaccharides: A promising strategy in the treatment of neurodegenerative disease. Neurochem Int 2024; 181:105902. [PMID: 39542041 DOI: 10.1016/j.neuint.2024.105902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/17/2024]
Abstract
Neurodegenerative diseases (NDDs), as a neurological disorder characterised by neuronal degeneration and death, are a serious threat to human health and have long attracted attention due to their complex pathogenesis and the ineffectiveness of therapeutic drugs. Existing studies have shown that Polygonatum Sibiricum polysaccharides (PSP) have immunoregulatory, antioxidant, anti-inflammatory and other pharmacological effects, and their neuroprotective effects have been demonstrated in several scientific studies. This paper reviews the main pharmacological effects and mechanisms of PSP in the protection and treatment of NDDs, to provide a reference for the clinical application and basic research of PSP in NDDs.
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Affiliation(s)
- Xue Jiang
- Shandong Medicine Technician College, 271000, Taian, China; Department of Pharmacy, The Affiliated Taian City Central Hospital of Qingdao University, 271000, Taian, China
| | - Yumei Wang
- Department of Pharmacy, The Affiliated Taian City Central Hospital of Qingdao University, 271000, Taian, China
| | - Zhaochen Lin
- Department of Pharmacy, The Affiliated Taian City Central Hospital of Qingdao University, 271000, Taian, China
| | - Chao Li
- Department of Pharmacy, The Affiliated Taian City Central Hospital of Qingdao University, 271000, Taian, China
| | - Qian Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018, Hangzhou, China
| | - Junyan Zhang
- College of Life Sciences, Northwest A & F University, 710000, Xi'an, China
| | - Xiuhua Liu
- Shandong Taishan Sealwort Biotechnology Limited Liability Company, 271000, Taian, China
| | - Ziye Li
- Xiangya School of Public Health, Central South University, 410078, Changsha, China
| | - Chao Cui
- Qilu Hospital of Shandong University Dezhou Hospital, 253000, Dezhou, China; Department of Pharmacy, The Affiliated Taian City Central Hospital of Qingdao University, 271000, Taian, China.
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Huang CC, Tsai SF, Liu SC, Yeh MC, Hung HC, Lee CW, Cheng CL, Hsu PL, Kuo YM. Insulin Mediates Lipopolysaccharide-Induced Inflammatory Responses and Oxidative Stress in BV2 Microglia. J Inflamm Res 2024; 17:7993-8008. [PMID: 39507265 PMCID: PMC11539848 DOI: 10.2147/jir.s481101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024] Open
Abstract
Introduction Insulin, the key hormone for glucose regulation, has garnered attention for its role as an immune modulator. Impaired insulin signaling in the central nervous system is linked to neuroinflammation and neurodegenerative diseases. Microglia, the resident macrophage-like immune cells in the brain, are key regulators of neuroinflammation. However, the mechanisms by which insulin influences microglial immune responses remain relatively unknown. Methods This study aimed to assess the effects of post-treatment with insulin [30 minutes after lipopolysaccharide (LPS) exposure] on LPS-induced inflammatory responses in BV2 microglial cells. Results Post-treatment with insulin potentiated LPS-induced production of nitric oxide and pro-inflammatory cytokines, such as TNF and IL-6, through activation of the Akt/NF-κB pathway. Insulin also enhanced the ability of BV2 cells to phagocytose bacteria particles and β-amyloid fibrils. Conversely, insulin inhibited activation of NADPH oxidase and reduced intracellular levels of reactive oxygen species in LPS-treated BV2 cells. Conclusion Insulin enhances microglial immune competence when challenged by endotoxins but mitigates oxidative stress in these cells.
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Affiliation(s)
- Chi-Chen Huang
- Division of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan
| | - Sheng-Feng Tsai
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Shu-Cheng Liu
- Department of Anesthesiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan
| | - Mei-Chen Yeh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chi Mei Medical Center, Tainan, 71004, Taiwan
| | - Hao-Chang Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chi Mei Medical Center, Tainan, 71004, Taiwan
| | - Chu-Wan Lee
- Department of Nursing, National Tainan Junior College of Nursing, Tainan, 700007, Taiwan
| | - Ching-Li Cheng
- Department of Nursing, National Tainan Junior College of Nursing, Tainan, 700007, Taiwan
| | - Pei-Ling Hsu
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Yu-Min Kuo
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
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Bhardwaj S, Grewal AK, Singh S, Dhankar V, Jindal A. An insight into the concept of neuroinflammation and neurodegeneration in Alzheimer's disease: targeting molecular approach Nrf2, NF-κB, and CREB. Inflammopharmacology 2024; 32:2943-2960. [PMID: 38951436 DOI: 10.1007/s10787-024-01502-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 06/04/2024] [Indexed: 07/03/2024]
Abstract
Alzheimer's disease (AD) is a most prevalent neurologic disorder characterized by cognitive dysfunction, amyloid-β (Aβ) protein accumulation, and excessive neuroinflammation. It affects various life tasks and reduces thinking, memory, capability, reasoning and orientation ability, decision, and language. The major parts responsible for these abnormalities are the cerebral cortex, amygdala, and hippocampus. Excessive inflammatory markers release, and microglial activation affect post-synaptic neurotransmission. Various mechanisms of AD pathogenesis have been explored, but still, there is a need to debate the role of NF-κB, Nrf2, inflammatory markers, CREB signaling, etc. In this review, we have briefly discussed the signaling mechanisms and function of the NF-ĸB signaling pathway, inflammatory mediators, microglia activation, and alteration of autophagy. NF-κB inhibition is a current strategy to counter neuroinflammation and neurodegeneration in the brain of individuals with AD. In clinical trials, numbers of NF-κB modulators are being examined. Recent reports revealed that molecular and cellular pathways initiate complex pathological competencies that cause AD. Moreover, this review will provide extensive knowledge of the cAMP response element binding protein (CREB) and how these nuclear proteins affect neuronal plasticity.
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Affiliation(s)
- Shaveta Bhardwaj
- G.H.G. Khalsa College of Pharmacy, Gurusar Sudhar, Ludhiana, India
| | - Amarjot Kaur Grewal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India.
| | - Shamsher Singh
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India.
| | - Vaibhav Dhankar
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
| | - Anu Jindal
- G.H.G. Khalsa College of Pharmacy, Gurusar Sudhar, Ludhiana, India
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16
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Kim Y, Ryu SH, Hyun J, Cho YS, Jung YK. TLR2 immunotherapy suppresses neuroinflammation, tau spread, and memory loss in rTg4510 mice. Brain Behav Immun 2024; 121:291-302. [PMID: 39098437 DOI: 10.1016/j.bbi.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024] Open
Abstract
In Alzheimer's disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer's disease.
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Affiliation(s)
- Youbin Kim
- Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Republic of Korea; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Shin-Hyeon Ryu
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Junho Hyun
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Young-Sin Cho
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yong-Keun Jung
- Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Republic of Korea; School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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Bhatt A, Bhardwaj H, Srivastava P. Mesenchymal stem cell therapy for Alzheimer's disease: A novel therapeutic approach for neurodegenerative diseases. Neuroscience 2024; 555:52-68. [PMID: 39032806 DOI: 10.1016/j.neuroscience.2024.07.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
Alzheimer's disease (AD) is one of the most progressive and prevalent types of neurodegenerative diseases in the aging population (aged >65 years) and is considered a major factor for dementia, affecting 55 million people worldwide. In the current scenario, drug-based therapies have been employed for the treatment of Alzheimer's disease but are only able to provide symptomatic relief to patients rather than a permanent solution from Alzheimer's. Recent advancements in stem cell research unlock new horizons for developing effective and highly potential therapeutic approaches due to their self-renewal, self-replicating, regenerative, and high differentiation capabilities. Stem cells come in multiple lineages such as embryonic, neural, and induced pluripotent, among others. Among different kinds of stem cells, mesenchymal stem cells are the most investigated for Alzheimer's treatment due to their multipotent nature, low immunogenicity, ability to penetrate the blood-brain barrier, and low risk of tumorigenesis, immune & inflammatory modulation, etc. They have been seen to substantially promote neurogenesis, synaptogenesis by secreting neurotrophic growth factors, as well as in ameliorating the Aβ and tau-mediated toxicity. This review covers the pathophysiology of AD, new medications, and therapies. Further, it will focus on the advancements and benefits of Mesenchymal Stem Cell therapies, their administration methods, clinical trials concerning AD progression, along with their future prospective.
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Affiliation(s)
- Aditya Bhatt
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Harshita Bhardwaj
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Priyanka Srivastava
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India.
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18
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Stavgiannoudaki I, Goulielmaki E, Garinis GA. Broken strands, broken minds: Exploring the nexus of DNA damage and neurodegeneration. DNA Repair (Amst) 2024; 140:103699. [PMID: 38852477 DOI: 10.1016/j.dnarep.2024.103699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 05/15/2024] [Accepted: 05/28/2024] [Indexed: 06/11/2024]
Abstract
Neurodegenerative disorders are primarily characterized by neuron loss progressively leading to cognitive decline and the manifestation of incurable and debilitating conditions, such as Alzheimer's, Parkinson's, and Huntington's diseases. Loss of genome maintenance causally contributes to age-related neurodegeneration, as exemplified by the premature appearance of neurodegenerative features in a growing family of human syndromes and mice harbouring inborn defects in DNA repair. Here, we discuss the relevance of persistent DNA damage, key DNA repair mechanisms and compromised genome integrity in age-related neurodegeneration highlighting the significance of investigating these connections to pave the way for the development of rationalized intervention strategies aimed at delaying the onset of neurodegenerative disorders and promoting healthy aging.
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Affiliation(s)
- Ioanna Stavgiannoudaki
- Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology-Hellas, Crete, Heraklion, Greece; Department of Biology, University of Crete, Crete, Heraklion, Greece
| | - Evi Goulielmaki
- Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology-Hellas, Crete, Heraklion, Greece
| | - George A Garinis
- Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology-Hellas, Crete, Heraklion, Greece; Department of Biology, University of Crete, Crete, Heraklion, Greece.
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Zhu T, Yao Y, Ding J, Zhang C, Xia N, Tao Y, Zhang W, Qi H, Gong L, Jiang P. 3-Methyladenine attenuates neuroinflammation and improves cognitive function in sepsis-associated encephalopathy by inhibiting autophagy. Int Immunopharmacol 2024; 139:112744. [PMID: 39059098 DOI: 10.1016/j.intimp.2024.112744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 07/01/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024]
Abstract
OBJECTIVE Sepsis-associated encephalopathy (SAE) can lead to severe cerebral dysfunction as well as cognitive dysfunction, resulting in a significant disease burden. 3-Methyladenine (3-MA) has been confirmed to have anti-inflammatory effects on diseases characterized by enhanced autophagy. However, its role in SAE has not been clarified. METHODS An SAE mouse model was generated by intraperitoneal injection of lipopolysaccharide (LPS). Mice were given 5, 20, or 80 mg/kg 3-MA to determine the therapeutic dose. The mice in the different groups were given 20 mg/kg 3-MA or saline, and survival, body temperature, body weight and neurobehavioral scores were measured at different time points. The expression of autophagy-related proteins and inflammatory factors was detected by Western blotting, enzyme linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR) 12 h after LPS induction. Glial activation and neuronal injury in the hippocampus were detected by immunofluorescence staining and HE staining. The open Field test, novel object recognition (NOR) test, Y-maze test, and Morris water maze (MWM) test were performed to assess cognitive function. RESULTS Treatment with 20 or 80 mg/kg 3-MA reduced the increase in hippocampal TNF-α, IL-6, and IL-1β expression in SAE model mice, with 20 mg/kg 3-MA having the greatest therapeutic effect. Treatment with 20 mg/kg 3-MA effectively reduced the expression of hippocampal autophagy-related proteins and mortality, ameliorated hypothermia, decreased body weight and electroencephalography (EEG) performance, and attenuated the activation of neuroglia and neuronal damage. Moreover, it alleviated the cognitive dysfunction 2 weeks after LPS induction. CONCLUSIONS 3-MA reduced neuroglial activation and neuronal damage, attenuated neuroinflammation, and improved cognitive deficits during recovery period by inhibiting autophagy in SAE.
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Affiliation(s)
- Tao Zhu
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310020, China
| | - Yinping Yao
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China; Department of Pediatrics, Shaoxing People's Hospital, Shaoxing, Zhejiang Province 312300, China
| | - Junchao Ding
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China; Department of Pediatrics, Yiwu Maternal and Child Health Care Hospital, Yiwu, Zhejiang Province 322000, China
| | - Chengyue Zhang
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China
| | - Ningxiao Xia
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China
| | - Yilin Tao
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China
| | - Wenhao Zhang
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China
| | - Hantao Qi
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China
| | - Lifen Gong
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China.
| | - Peifang Jiang
- Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province 310052, China.
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20
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Ho G, Lam L, Tran T, Wei J, Hashimoto M. Innate neuroimmunity across aging and neurodegeneration: a perspective from amyloidogenic evolvability. Front Cell Dev Biol 2024; 12:1430593. [PMID: 39071802 PMCID: PMC11272618 DOI: 10.3389/fcell.2024.1430593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 06/17/2024] [Indexed: 07/30/2024] Open
Abstract
In Alzheimer's Disease (AD), amyloidogenic proteins (APs), such as β-amyloid (Aβ) and tau, may act as alarmins/damage-associated molecular patterns (DAMPs) to stimulate neuroinflammation and cell death. Indeed, recent evidence suggests that brain-specific type 2 immune networks may be important in modulating amyloidogenicity and brain homeostasis. Central to this, components of innate neuroimmune signaling, particularly type 2 components, assume distinctly specialized roles in regulating immune homeostasis and brain function. Whereas balanced immune surveillance stems from normal type 2 brain immune function, appropriate microglial clearance of aggregated misfolded proteins and neurotrophic and synaptotrophic signaling, aberrant pro-inflammatory activity triggered by alarmins might disrupt this normal immune homeostasis with reduced microglial amyloid clearance, synaptic loss, and ultimately neurodegeneration. Furthermore, since increased inflammation may in turn cause neurodegeneration, it is predicted that AP aggregation and neuroinflammation could synergistically promote even more damage. The reasons for maintaining such adverse biological conditions which have not been weeded out during evolution remain unclear. Here, we discuss these issues from a viewpoint of amyloidogenic evolvability, namely, aEVO, a hypothetic view of an adaptation to environmental stress by AP aggregates. Speculatively, the interaction of AP aggregation and neuroinflammation for aEVO in reproduction, which is evolutionally beneficial, might become a co-activating relationship which promotes AD pathogenesis through antagonistic pleiotropy. If validated, simultaneously suppressing both AP aggregation and specific innate neuroinflammation could greatly increase therapeutic efficacy in AD. Overall, combining a better understanding of innate neuroimmunity in aging and disease with the aEVO hypothesis may help uncover novel mechanism of pathogenesis of AD, leading to improved diagnostics and treatments.
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Affiliation(s)
- Gilbert Ho
- PCND Neuroscience Research Institute, Poway, CA, United States
| | - Linh Lam
- PCND Neuroscience Research Institute, Poway, CA, United States
| | - Tony Tran
- PCND Neuroscience Research Institute, Poway, CA, United States
| | - Jianshe Wei
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng, China
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Zhu Y, Zhang Y, He S, Yi S, Feng H, Xia X, Fang X, Gong X, Zhao P. Integrating single-nucleus RNA sequencing and spatial transcriptomics to elucidate a specialized subpopulation of astrocytes, microglia and vascular cells in brains of mouse model of lipopolysaccharide-induced sepsis-associated encephalopathy. J Neuroinflammation 2024; 21:169. [PMID: 38961424 PMCID: PMC11223438 DOI: 10.1186/s12974-024-03161-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 06/26/2024] [Indexed: 07/05/2024] Open
Abstract
BACKGROUND Understanding the mechanism behind sepsis-associated encephalopathy (SAE) remains a formidable task. This study endeavors to shed light on the complex cellular and molecular alterations that occur in the brains of a mouse model with SAE, ultimately unraveling the underlying mechanisms of this condition. METHODS We established a murine model using intraperitoneal injection of lipopolysaccharide (LPS) in wild type and Anxa1-/- mice and collected brain tissues for analysis at 0-hour, 12-hour, 24-hour, and 72-hour post-injection. Utilizing advanced techniques such as single-nucleus RNA sequencing (snRNA-seq) and Stereo-seq, we conducted a comprehensive characterization of the cellular responses and molecular patterns within the brain. RESULTS Our study uncovered notable temporal differences in the response to LPS challenge between Anxa1-/- (annexin A1 knockout) and wild type mice, specifically at the 12-hour and 24-hour time points following injection. We observed a significant increase in the proportion of Astro-2 and Micro-2 cells in these mice. These cells exhibited a colocalization pattern with the vascular subtype Vas-1, forming a distinct region known as V1A2M2, where Astro-2 and Micro-2 cells surrounded Vas-1. Moreover, through further analysis, we discovered significant upregulation of ligands and receptors such as Timp1-Cd63, Timp1-Itgb1, Timp1-Lrp1, as well as Ccl2-Ackr1 and Cxcl2-Ackr1 within this region. In addition, we observed a notable increase in the expression of Cd14-Itgb1, Cd14-Tlr2, and Cd14-C3ar1 in regions enriched with Micro-2 cells. Additionally, Cxcl10-Sdc4 showed broad upregulation in brain regions containing both Micro-2 and Astro-2 cells. Notably, upon LPS challenge, there was an observed increase in Anxa1 expression in the mouse brain. Furthermore, our study revealed a noteworthy increase in mortality rates following Anxa1 knockdown. However, we did not observe substantial differences in the types, numbers, or distribution of other brain cells between Anxa1-/- and wildtype mice over time. Nevertheless, when comparing the 24-hour post LPS injection time point, we observed a significant decrease in the proportion and distribution of Micro-2 and Astro-2 cells in the vicinity of blood vessels in Anxa1-/- mice. Additionally, we noted reduced expression levels of several ligand-receptor pairs including Cd14-Tlr2, Cd14-C3ar1, Cd14-Itgb1, Cxcl10-Sdc4, Ccl2-Ackr1, and Cxcl2-Ackr1. CONCLUSIONS By combining snRNA-seq and Stereo-seq techniques, our study successfully identified a distinctive cellular colocalization, referred to as a special pathological niche, comprising Astro-2, Micro-2, and Vas-1 cells. Furthermore, we observed an upregulation of ligand-receptor pairs within this niche. These findings suggest a potential association between this cellular arrangement and the underlying mechanisms contributing to SAE or the increased mortality observed in Anxa1 knockdown mice.
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Grants
- 2021A1515012429 Natural Science Foundation of Guangdong Province, China
- 211102114530659 Shaoguan Municipal Science and Technology Program, China
- 20221807 Shaoguan Engineering Research Center for Research and Development of Molecular and Cellular Technology in Rapid Diagnosis of Infectious Diseases and Cancer Program, China
- KEYANSHEN (2023) 01 Research Fund for Joint Laboratory for Digital and Precise Detection of Clinical Pathogens, Yuebei People's Hospital Affiliated to Shantou University Medical College, China
- RS202001 Research Project for Outstanding Scholar of Yuebei People's Hospital, Shantou University Medical College, China
- Research Fund for Joint Laboratory for Digital and Precise Detection of Clinical Pathogens, Yuebei People’s Hospital Affiliated to Shantou University Medical College, China
- Research Project for Outstanding Scholar of Yuebei People’s Hospital, Shantou University Medical College, China
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Affiliation(s)
- Yanyan Zhu
- Department of Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, No 133, Huimin Road South, Wujiang District, Shaoguan, 512025, China
- Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China
- Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine, Shaoguan, 512025, China
- Shaoguan Municipal Quality Control Center for Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China
- Shaoguan Municipal Quality Control Center for Surveillance of Bacterial Resistance, Shaoguan, 512025, China
- Shaoguan Engineering Research Center for Research and Development of Molecular and Cellular Technology in Rapid Diagnosis of Infectious Diseases and Cancer, Shaoguan, 512025, China
| | - Yin Zhang
- BGI-Shenzhen, Shenzhen, 518083, China
| | - Sheng He
- Department of Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, No 133, Huimin Road South, Wujiang District, Shaoguan, 512025, China
- Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China
- Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine, Shaoguan, 512025, China
- Shaoguan Municipal Quality Control Center for Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China
- Shaoguan Municipal Quality Control Center for Surveillance of Bacterial Resistance, Shaoguan, 512025, China
- Shaoguan Engineering Research Center for Research and Development of Molecular and Cellular Technology in Rapid Diagnosis of Infectious Diseases and Cancer, Shaoguan, 512025, China
| | - Sanjun Yi
- Department of Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, No 133, Huimin Road South, Wujiang District, Shaoguan, 512025, China
- Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China
- Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine, Shaoguan, 512025, China
- Shaoguan Municipal Quality Control Center for Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China
- Shaoguan Municipal Quality Control Center for Surveillance of Bacterial Resistance, Shaoguan, 512025, China
- Shaoguan Engineering Research Center for Research and Development of Molecular and Cellular Technology in Rapid Diagnosis of Infectious Diseases and Cancer, Shaoguan, 512025, China
| | - Hao Feng
- Jiaxing University Master Degree Cultivation Base, Zhejiang Chinese Medical University, Jiaxing, 314001, China
| | - Xianzhu Xia
- Department of Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, No 133, Huimin Road South, Wujiang District, Shaoguan, 512025, China
- Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China
- Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine, Shaoguan, 512025, China
| | | | - Xiaoqian Gong
- Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China.
| | - Pingsen Zhao
- Department of Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, No 133, Huimin Road South, Wujiang District, Shaoguan, 512025, China.
- Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China.
- Research Center for Interdisciplinary & High-quality Innovative Development in Laboratory Medicine, Shaoguan, 512025, China.
- Shaoguan Municipal Quality Control Center for Laboratory Medicine, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, 512025, China.
- Shaoguan Municipal Quality Control Center for Surveillance of Bacterial Resistance, Shaoguan, 512025, China.
- Shaoguan Engineering Research Center for Research and Development of Molecular and Cellular Technology in Rapid Diagnosis of Infectious Diseases and Cancer, Shaoguan, 512025, China.
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22
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Kumar Nelson V, Jha NK, Nuli MV, Gupta S, Kanna S, Gahtani RM, Hani U, Singh AK, Abomughaid MM, Abomughayedh AM, Almutary AG, Iqbal D, Al Othaim A, Begum SS, Ahmad F, Mishra PC, Jha SK, Ojha S. Unveiling the impact of aging on BBB and Alzheimer's disease: Factors and therapeutic implications. Ageing Res Rev 2024; 98:102224. [PMID: 38346505 DOI: 10.1016/j.arr.2024.102224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 02/01/2024] [Accepted: 02/03/2024] [Indexed: 05/12/2024]
Abstract
Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that has devastating effects on individuals, often resulting in dementia. AD is primarily defined by the presence of extracellular plaques containing insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (P-tau). In addition, individuals afflicted by these age-related illnesses experience a diminished state of health, which places significant financial strain on their loved ones. Several risk factors play a significant role in the development of AD. These factors include genetics, diet, smoking, certain diseases (such as cerebrovascular diseases, obesity, hypertension, and dyslipidemia), age, and alcohol consumption. Age-related factors are key contributors to the development of vascular-based neurodegenerative diseases such as AD. In general, the process of aging can lead to changes in the immune system's responses and can also initiate inflammation in the brain. The chronic inflammation and the inflammatory mediators found in the brain play a crucial role in the dysfunction of the blood-brain barrier (BBB). Furthermore, maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. Therefore, in this review, we discussed the role of age and its related factors in the breakdown of the blood-brain barrier and the development of AD. We also discussed the importance of different compounds, such as those with anti-aging properties, and other compounds that can help maintain the integrity of the blood-brain barrier in the prevention of AD. This review builds a strong correlation between age-related factors, degradation of the BBB, and its impact on AD.
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Affiliation(s)
- Vinod Kumar Nelson
- Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, India.
| | - Niraj Kumar Jha
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Centre of Research Impact and Outcome, Chitkara University, Rajpura 140401, Punjab, India; School of Bioengineering & Biosciences, Lovely Professional University, Phagwara 144411, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India.
| | - Mohana Vamsi Nuli
- Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, India
| | - Sandeep Kanna
- Department of pharmaceutics, Chalapathi Institute of Pharmaceutical Sciences, Chalapathi Nagar, Guntur 522034, India
| | - Reem M Gahtani
- Departement of Clinical Laboratory Sciences, King Khalid University, Abha, Saudi Arabia
| | - Umme Hani
- Department of pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Arun Kumar Singh
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology BHU, Varanasi, Uttar Pradesh, India
| | - Mosleh Mohammad Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
| | - Ali M Abomughayedh
- Pharmacy Department, Aseer Central Hospital, Ministry of Health, Saudi Arabia
| | - Abdulmajeed G Almutary
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, P.O. Box 59911, United Arab Emirates
| | - Danish Iqbal
- Department of Health Information Management, College of Applied Medical Sciences, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia
| | - Ayoub Al Othaim
- Department of Medical Laboratory Sciences, College of Applied Medical Science, Majmaah University, Al-Majmaah 11952, Saudi Arabia.
| | - S Sabarunisha Begum
- Department of Biotechnology, P.S.R. Engineering College, Sivakasi 626140, India
| | - Fuzail Ahmad
- Respiratory Care Department, College of Applied Sciences, Almaarefa University, Diriya, Riyadh, 13713, Saudi Arabia
| | - Prabhu Chandra Mishra
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Saurabh Kumar Jha
- Department of Zoology, Kalindi College, University of Delhi, 110008, India.
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, P.O. Box 15551, United Arab Emirates
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23
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Juvenal G, Meinerz C, Ayupe AC, Campos HC, Reis EM, Longo BM, Pillat MM, Ulrich H. Bradykinin promotes immune responses in differentiated embryonic neurospheres carrying APP swe and PS1 dE9 mutations. Cell Biosci 2024; 14:82. [PMID: 38890712 PMCID: PMC11184896 DOI: 10.1186/s13578-024-01251-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/24/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Neural progenitor cells (NPCs) can be cultivated from developing brains, reproducing many of the processes that occur during neural development. They can be isolated from a variety of animal models, such as transgenic mice carrying mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN 1 and 2), characteristic of familial Alzheimer's disease (fAD). Modulating the development of these cells with inflammation-related peptides, such as bradykinin (BK) and its antagonist HOE-140, enables the understanding of the impact of such molecules in a relevant AD model. RESULTS We performed a global gene expression analysis on transgenic neurospheres treated with BK and HOE-140. To validate the microarray data, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) was performed on 8 important genes related to the immune response in AD such as CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF alpha and Iba-1. Furthermore, comparative analysis of the transcriptional profiles was performed between treatments, including gene ontology and reactome enrichment, construction and analysis of protein-protein interaction networks and, finally, comparison of our data with human dataset from AD patients. The treatments affected the expression levels of genes mainly related to microglia-mediated neuroinflammatory responses, with BK promoting an increase in the expression of genes that enrich processes, biological pathways, and cellular components related to immune dysfunction, neurodegeneration and cell cycle. B2 receptor inhibition by HOE-140 resulted in the reduction of AD-related anomalies caused in this system. CONCLUSIONS BK is an important immunomodulatory agent and enhances the immunological changes identified in transgenic neurospheres carrying the genetic load of AD. Bradykinin treatments modulate the expression rates of genes related to microglia-mediated neuroinflammation. Inhibiting bradykinin activity in Alzheimer's disease may slow disease progression.
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Affiliation(s)
- Guilherme Juvenal
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-900, Brazil
| | - Carine Meinerz
- Department of Microbiology and Parasitology, Health Sciences Center, Federal University of Santa Maria, Santa Maria-RS, Brazil
| | - Ana Carolina Ayupe
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-900, Brazil
| | | | - Eduardo Moraes Reis
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-900, Brazil
| | | | - Micheli Mainardi Pillat
- Department of Microbiology and Parasitology, Health Sciences Center, Federal University of Santa Maria, Santa Maria-RS, Brazil.
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-900, Brazil.
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24
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Zhang Q, Yang G, Luo Y, Jiang L, Chi H, Tian G. Neuroinflammation in Alzheimer's disease: insights from peripheral immune cells. Immun Ageing 2024; 21:38. [PMID: 38877498 PMCID: PMC11177389 DOI: 10.1186/s12979-024-00445-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 06/07/2024] [Indexed: 06/16/2024]
Abstract
Alzheimer's disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and cerebrovascular dysfunction. The presence of chronic neuroinflammation, breaches in the blood-brain barrier (BBB), and increased levels of inflammatory mediators are central to the pathogenesis of AD. These factors promote the penetration of immune cells into the brain, potentially exacerbating clinical symptoms and neuronal death in AD patients. While microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD, recent evidence suggests the infiltration of cerebral vessels and parenchyma by peripheral immune cells, including neutrophils, T lymphocytes, B lymphocytes, NK cells, and monocytes in AD. These cells participate in the regulation of immunity and inflammation, which is expected to play a huge role in future immunotherapy. Given the crucial role of peripheral immune cells in AD, this article seeks to offer a comprehensive overview of their contributions to neuroinflammation in the disease. Understanding the role of these cells in the neuroinflammatory response is vital for developing new diagnostic markers and therapeutic targets to enhance the diagnosis and treatment of AD patients.
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Affiliation(s)
- Qiang Zhang
- Department of Laboratory Medicine, Southwest Medical University, Luzhou, China
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH, USA
| | - Yuan Luo
- Department of Laboratory Medicine, Southwest Medical University, Luzhou, China
| | - Lai Jiang
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China.
| | - Gang Tian
- Department of Laboratory Medicine, Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University, Sichuan, 646000, China.
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25
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Li B, Suresh P, Brelstaff J, Kedia S, Bryant CE, Klenerman D. The delayed kinetics of Myddosome formation explains why amyloid-beta aggregates trigger Toll-like receptor 4 less efficiently than lipopolysaccharide. eLife 2024; 13:RP92350. [PMID: 38864842 PMCID: PMC11168745 DOI: 10.7554/elife.92350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2024] Open
Abstract
The Myddosome is a key innate immune signalling platform. It forms at the cell surface and contains MyD88 and IRAK proteins which ultimately coordinate the production of pro-inflammatory cytokines. Toll-like receptor 4 (TLR4) signals via the Myddosome when triggered by lipopolysaccharide (LPS) or amyloid-beta (Aβ) aggregates but the magnitude and time duration of the response are very different for reasons that are unclear. Here, we followed the formation of Myddosomes in live macrophages using local delivery of TLR4 agonist to the cell surface and visualisation with 3D rapid light sheet imaging. This was complemented by super-resolution imaging of Myddosomes in fixed macrophages to determine the size of the signalling complex at different times after triggering. Myddosomes formed more rapidly after LPS than in response to sonicated Aβ 1-42 fibrils (80 vs 372 s). The mean lifetimes of the Myddosomes were also shorter when triggered by LPS compared to sonicated Aβ fibrils (170 and 220 s), respectively. In both cases, a range of Myddosome of different sizes (50-500 nm) were formed. In particular, small round Myddosomes around 100 nm in size formed at early time points, then reduced in proportion over time. Collectively, our data suggest that compared to LPS the multivalency of Aβ fibrils leads to the formation of larger Myddosomes which form more slowly and, due to their size, take longer to disassemble. This explains why sonicated Aβ fibrils results in less efficient triggering of TLR4 signalling and may be a general property of protein aggregates.
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Affiliation(s)
- Bing Li
- Department of Chemistry, University of CambridgeCambridgeUnited Kingdom
- Cambridge Dementia Research Centre, Clifford Allbutt Building, Cambridge Biomedical CampusCambridgeUnited Kingdom
| | - Prasanna Suresh
- Department of Chemistry, University of CambridgeCambridgeUnited Kingdom
- Cambridge Dementia Research Centre, Clifford Allbutt Building, Cambridge Biomedical CampusCambridgeUnited Kingdom
| | - Jack Brelstaff
- Department of Medicine, Addenbrooke’s Hospital, Cambridge Biomedical CampusCambridgeUnited Kingdom
| | - Shekhar Kedia
- Department of Chemistry, University of CambridgeCambridgeUnited Kingdom
- Cambridge Dementia Research Centre, Clifford Allbutt Building, Cambridge Biomedical CampusCambridgeUnited Kingdom
| | - Clare E Bryant
- Department of Medicine, Addenbrooke’s Hospital, Cambridge Biomedical CampusCambridgeUnited Kingdom
| | - David Klenerman
- Department of Chemistry, University of CambridgeCambridgeUnited Kingdom
- Cambridge Dementia Research Centre, Clifford Allbutt Building, Cambridge Biomedical CampusCambridgeUnited Kingdom
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26
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Young AP, Denovan-Wright EM. JAK1/2 Regulates Synergy Between Interferon Gamma and Lipopolysaccharides in Microglia. J Neuroimmune Pharmacol 2024; 19:14. [PMID: 38642237 DOI: 10.1007/s11481-024-10115-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/01/2024] [Indexed: 04/22/2024]
Abstract
Microglia, the resident immune cells of the brain, regulate neuroinflammation which can lead to secondary neuronal damage and cognitive impairment under pathological conditions. Two of the many molecules that can elicit an inflammatory response from microglia are lipopolysaccharide (LPS), a component of gram-negative bacteria, and interferon gamma (IFNγ), an endogenous pro-inflammatory cytokine. We thoroughly examined the concentration-dependent relationship between LPS from multiple bacterial species and IFNγ in cultured microglia and macrophages. We measured the effects that these immunostimulatory molecules have on pro-inflammatory activity of microglia and used a battery of signaling inhibitors to identify the pathways that contribute to the microglial response. We found that LPS and IFNγ interacted synergistically to induce a pro-inflammatory phenotype in microglia, and that inhibition of JAK1/2 completely blunted the response. We determined that this synergistic action of LPS and IFNγ was likely dependent on JNK and Akt signaling rather than typical pro-inflammatory mediators such as NF-κB. Finally, we demonstrated that LPS derived from Escherichia coli, Klebsiella pneumoniae, and Akkermansia muciniphila can elicit different inflammatory responses from microglia and macrophages, but these responses could be consistently prevented using ruxolitinib, a JAK1/2 inhibitor. Collectively, this work reveals a mechanism by which microglia may become hyperactivated in response to the combination of LPS and IFNγ. Given that elevations in circulating LPS and IFNγ occur in a wide variety of pathological conditions, it is critical to understand the pharmacological interactions between these molecules to develop safe and effective treatments to suppress this process.
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Affiliation(s)
- Alexander P Young
- Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
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27
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Reich N, Hölscher C. Cholecystokinin (CCK): a neuromodulator with therapeutic potential in Alzheimer's and Parkinson's disease. Front Neuroendocrinol 2024; 73:101122. [PMID: 38346453 DOI: 10.1016/j.yfrne.2024.101122] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/04/2024] [Accepted: 01/25/2024] [Indexed: 02/16/2024]
Abstract
Cholecystokinin (CCK) is a neuropeptide modulating digestion, glucose levels, neurotransmitters and memory. Recent studies suggest that CCK exhibits neuroprotective effects in Alzheimer's disease (AD) and Parkinson's disease (PD). Thus, we review the physiological function and therapeutic potential of CCK. The neuropeptide facilitates hippocampal glutamate release and gates GABAergic basket cell activity, which improves declarative memory acquisition, but inhibits consolidation. Cortical CCK alters recognition memory and enhances audio-visual processing. By stimulating CCK-1 receptors (CCK-1Rs), sulphated CCK-8 elicits dopamine release in the substantia nigra and striatum. In the mesolimbic pathway, CCK release is triggered by dopamine and terminates reward responses via CCK-2Rs. Importantly, activation of hippocampal and nigral CCK-2Rs is neuroprotective by evoking AMPK activation, expression of mitochondrial fusion modulators and autophagy. Other benefits include vagus nerve/CCK-1R-mediated expression of brain-derived neurotrophic factor, intestinal protection and suppression of inflammation. We also discuss caveats and the therapeutic combination of CCK with other peptide hormones.
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Affiliation(s)
- Niklas Reich
- The ALBORADA Drug Discovery Institute, University of Cambridge, Island Research Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0AH, UK; Faculty of Health and Medicine, Biomedical & Life Sciences Division, Lancaster University, Lancaster LA1 4YQ, UK.
| | - Christian Hölscher
- Second associated Hospital, Neurology Department, Shanxi Medical University, Taiyuan, Shanxi, China; Henan Academy of Innovations in Medical Science, Neurodegeneration research group, Xinzhen, Henan province, China
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28
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Ng RCL, Jian M, Ma OKF, Xiang AW, Bunting M, Kwan JSC, Wong CWK, Yick LW, Chung SK, Lam KSL, Alexander IE, Xu A, Chan KH. Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer's disease. J Neuroinflammation 2024; 21:77. [PMID: 38539253 PMCID: PMC10967198 DOI: 10.1186/s12974-024-03066-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 03/17/2024] [Indexed: 01/05/2025] Open
Abstract
Adiponectin (APN) is an adipokine which predominantly expresses in adipocytes with neuroprotective and anti-inflammatory effects. We have recently indicated that circulatory trimeric APN can enter the brain by crossing the blood-brain barrier (BBB) and modulate microglia-mediated neuroinflammation. Here, we found that the microglial NLR family pyrin domain containing 3 (NLRP3)-inflammasome activation was exacerbated in APN-/-5xFAD mice in age-dependent manner. The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer's disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated APN gene (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aβ in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aβ-induced IL-1β and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD.
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Affiliation(s)
- Roy Chun-Laam Ng
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, UK
| | - Min Jian
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Oscar Ka-Fai Ma
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ariya Weiman Xiang
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Myriam Bunting
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jason Shing-Cheong Kwan
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Curtis Wai-Kin Wong
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Leung-Wah Yick
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Sookja Kim Chung
- Faculty of Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery at Macau University of Science and Technology, Taipa, Macao, China
| | - Karen Siu-Ling Lam
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Ian E Alexander
- Gene Therapy Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute and Sydney Children's Hospitals Network, The University of Sydney, Westmead, NSW, Australia
| | - Aimin Xu
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China
- Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Koon-Ho Chan
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China.
- Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
- Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China.
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Ye Y, Gao M, Shi W, Gao Y, Li Y, Yang W, Zheng X, Lu X. The immunomodulatory effects of mesenchymal stem cell-derived extracellular vesicles in Alzheimer's disease. Front Immunol 2024; 14:1325530. [PMID: 38259476 PMCID: PMC10800421 DOI: 10.3389/fimmu.2023.1325530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
Neuroinflammation has been identified as another significant pathogenic factor in Alzheimer's disease following Aβ amyloid deposition and tau protein hyperphosphorylation, activated in the central nervous system by glial cells in response to injury-related and pathogen-related molecular patterns. Moderate glial cell activity can be neuroprotective; however, excessive glial cell activation advances the pathology of Alzheimer's disease and is accompanied by structural changes in the brain interface, with peripheral immune cells entering the brain through the blood-brain barrier, creating a vicious circle. The immunomodulatory properties of mesenchymal stem cells (MSCs) are primarily conveyed through extracellular vesicles (EVs). MSC-EVs participate in chronic inflammatory and immune processes by transferring nucleic acids, proteins and lipids from the parent cell to the recipient cell, thus MSC-EVs retain their immunomodulatory capacity while avoiding the safety issues associated with living cell therapy, making them a promising focus for immunomodulatory therapy. In this review, we discuss the modulatory effects of MSC-EVs on Alzheimer's disease-associated immune cells and the mechanisms involved in their treatment of the condition. We have found a clinical trial of MSC-EVs in Alzheimer's disease treatment and outlined the challenges of this approach. Overall, MSC-EVs have the potential to provide a safe and effective treatment option for Alzheimer's disease by targeting neuroinflammation.
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Affiliation(s)
- Yang Ye
- Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Mingzhu Gao
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Central Hospital of Jiangnan University, Wuxi No.2 People’s Hospital, Wuxi, China
| | - Wentao Shi
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yan Gao
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yilu Li
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Wenhui Yang
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiaomin Zheng
- Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiaojie Lu
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Central Hospital of Jiangnan University, Wuxi No.2 People’s Hospital, Wuxi, China
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30
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Gebril HM, Aryasomayajula A, de Lima MRN, Uhrich KE, Moghe PV. Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer's pathology. Transl Neurodegener 2024; 13:2. [PMID: 38173014 PMCID: PMC10765804 DOI: 10.1186/s40035-023-00393-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 12/12/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection. METHODS We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM-NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM-NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. RESULTS AM-NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM-NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ. CONCLUSIONS The AM-NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons.
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Affiliation(s)
- Hoda M Gebril
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd., Piscataway, NJ, 08854, USA.
| | - Aravind Aryasomayajula
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd., Piscataway, NJ, 08854, USA
| | | | - Kathryn E Uhrich
- Department of Chemistry, University of California, 501 Big Springs Rd., Riverside, CA, 92507, USA
| | - Prabhas V Moghe
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd., Piscataway, NJ, 08854, USA.
- Department of Chemical and Biochemical Engineering, Rutgers University, 98 Brett Rd., Piscataway, NJ, 08854, USA.
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Church KA, Cardona AE, Hopp SC. Roles in Innate Immunity. ADVANCES IN NEUROBIOLOGY 2024; 37:263-286. [PMID: 39207697 DOI: 10.1007/978-3-031-55529-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Microglia are best known as the resident phagocytes of the central nervous system (CNS). As a resident brain immune cell population, microglia play key roles during the initiation, propagation, and resolution of inflammation. The discovery of resident adaptive immune cells in the CNS has unveiled a relationship between microglia and adaptive immune cells for CNS immune-surveillance during health and disease. The interaction of microglia with elements of the peripheral immune system and other CNS resident cells mediates a fine balance between neuroprotection and tissue damage. In this chapter, we highlight the innate immune properties of microglia, with a focus on how pattern recognition receptors, inflammatory signaling cascades, phagocytosis, and the interaction between microglia and adaptive immune cells regulate events that initiate an inflammatory or neuroprotective response within the CNS that modulates immune-mediated disease exacerbation or resolution.
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Affiliation(s)
- Kaira A Church
- Department of Molecular Microbiology & Immunology, The University of Texas at San Antonio, San Antonio, TX, USA
- South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX, USA
| | - Astrid E Cardona
- Department of Molecular Microbiology & Immunology, The University of Texas at San Antonio, San Antonio, TX, USA
- South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX, USA
| | - Sarah C Hopp
- Department of Pharmacology, Biggs Institute for Alzheimer's and Neurodegenerative Disease, The University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
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32
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Terzioglu G, Young-Pearse TL. Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer's disease. Mol Neurodegener 2023; 18:89. [PMID: 38017562 PMCID: PMC10685641 DOI: 10.1186/s13024-023-00674-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 10/26/2023] [Indexed: 11/30/2023] Open
Abstract
Recent genetic studies on Alzheimer's disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed in microglia. Several of these genes have been recognized for their central roles in microglial functions. Increasing evidence suggests that SHIP1, the protein encoded by the AD-associated gene INPP5D, is an important regulator of microglial phagocytosis and immune response. A recent study from our group identified SHIP1 as a negative regulator of the NLRP3 inflammasome in human iPSC-derived microglial cells (iMGs). In addition, we found evidence for a connection between SHIP1 activity and inflammasome activation in the AD brain. The NLRP3 inflammasome is a multiprotein complex that induces the secretion of pro-inflammatory cytokines as part of innate immune responses against pathogens and endogenous damage signals. Previously published studies have suggested that the NLRP3 inflammasome is activated in AD and contributes to AD-related pathology. Here, we provide an overview of the current understanding of the microglial NLRP3 inflammasome in the context of AD-related inflammation. We then review the known intracellular functions of SHIP1, including its role in phosphoinositide signaling, interactions with microglial phagocytic receptors such as TREM2 and evidence for its intersection with NLRP3 inflammasome signaling. Through rigorous examination of the intricate connections between microglial signaling pathways across several experimental systems and postmortem analyses, the field will be better equipped to tailor newly emerging therapeutic strategies targeting microglia in neurodegenerative diseases.
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Affiliation(s)
- Gizem Terzioglu
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd, Boston, MA, 02115, USA
| | - Tracy L Young-Pearse
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd, Boston, MA, 02115, USA.
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33
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García-Bermúdez MY, Vohra R, Freude K, van Wijngaarden P, Martin K, Thomsen MS, Aldana BI, Kolko M. Potential Retinal Biomarkers in Alzheimer's Disease. Int J Mol Sci 2023; 24:15834. [PMID: 37958816 PMCID: PMC10649108 DOI: 10.3390/ijms242115834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/18/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Alzheimer's disease (AD) represents a major diagnostic challenge, as early detection is crucial for effective intervention. This review examines the diagnostic challenges facing current AD evaluations and explores the emerging field of retinal alterations as early indicators. Recognizing the potential of the retina as a noninvasive window to the brain, we emphasize the importance of identifying retinal biomarkers in the early stages of AD. However, the examination of AD is not without its challenges, as the similarities shared with other retinal diseases introduce complexity in the search for AD-specific markers. In this review, we address the relevance of using the retina for the early diagnosis of AD and the complex challenges associated with the search for AD-specific retinal biomarkers. We provide a comprehensive overview of the current landscape and highlight avenues for progress in AD diagnosis by retinal examination.
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Affiliation(s)
| | - Rupali Vohra
- Eye Translational Research Unit, Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
- Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark
| | - Kristine Freude
- Group of Stem Cell Models and Embryology, Department of Veterinary and Animal Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark
| | - Peter van Wijngaarden
- Center for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Keith Martin
- Center for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Maj Schneider Thomsen
- Neurobiology Research and Drug Delivery, Department of Health, Science and Technology, Aalborg University, 9220 Aalborg, Denmark
| | - Blanca Irene Aldana
- Neurometabolism Research Group, Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Miriam Kolko
- Eye Translational Research Unit, Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
- Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark
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Balu D, Valencia-Olvera AC, Nguyen A, Patnam M, York J, Peri F, Neumann F, LaDu MJ, Tai LM. A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice. Alzheimers Res Ther 2023; 15:181. [PMID: 37858252 PMCID: PMC10585767 DOI: 10.1186/s13195-023-01330-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 10/10/2023] [Indexed: 10/21/2023]
Abstract
BACKGROUND APOE genotype is the greatest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 increases AD risk up to 12-fold compared to APOE3, an effect that is greater in females. Evidence suggests that one-way APOE could modulate AD risk and progression through neuroinflammation. Indeed, APOE4 is associated with higher glial activation and cytokine levels in AD patients and mice. Therefore, identifying pathways that contribute to APOE4-associated neuroinflammation is an important approach for understanding and treating AD. Human and in vivo evidence suggests that TLR4, one of the key receptors involved in the innate immune system, could be involved in APOE-modulated neuroinflammation. Consistent with that idea, we previously demonstrated that the TLR4 antagonist IAXO-101 can reduce LPS- and Aβ-induced cytokine secretion in APOE4 glial cultures. Therefore, the goal of this study was to advance these findings and determine whether IAXO-101 can modulate neuroinflammation, Aβ pathology, and behavior in mice that express APOE4. METHODS We used mice that express five familial AD mutations and human APOE3 (E3FAD) or APOE4 (E4FAD). Female and male E4FAD mice and female E3FAD mice were treated with vehicle or IAXO-101 in two treatment paradigms: prevention from 4 to 6 months of age or reversal from 6 to 7 months of age. Learning and memory were assessed by modified Morris water maze. Aβ deposition, fibrillar amyloid deposition, astrogliosis, and microgliosis were assessed by immunohistochemistry. Soluble levels of Aβ and apoE, insoluble levels of apoE and Aβ, and IL-1β were measured by ELISA. RESULTS IAXO-101 treatment resulted in lower Iba-1 coverage, lower number of reactive microglia, and improved memory in female E4FAD mice in both prevention and reversal paradigms. IAXO-101-treated male E4FAD mice also had lower Iba-1 coverage and reactivity in the RVS paradigm, but there was no effect on behavior. There was also no effect of IAXO-101 treatment on neuroinflammation and behavior in female E3FAD mice. CONCLUSION Our data supports that TLR4 is a potential mechanistic therapeutic target for modulating neuroinflammation and cognition in APOE4 females.
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Affiliation(s)
- Deebika Balu
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Ana C Valencia-Olvera
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Austin Nguyen
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Mehul Patnam
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Jason York
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Francesco Peri
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | | | - Mary Jo LaDu
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Leon M Tai
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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35
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Weaver DF. Druggable targets for the immunopathy of Alzheimer's disease. RSC Med Chem 2023; 14:1645-1661. [PMID: 37731705 PMCID: PMC10507808 DOI: 10.1039/d3md00096f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 06/21/2023] [Indexed: 09/22/2023] Open
Abstract
Alzheimer's disease (AD) is one of the leading threats to the health and socioeconomic well-being of humankind. Though research to develop disease modifying therapies for AD has traditionally focussed on the misfolding and aggregation of proteins, this approach has failed to yield a definitively curative agent. Accordingly, the search for additional or alternative approaches is a medicinal chemistry priority. Dysfunction of the brain's neuroimmune-neuroinflammation axis has emerged as a leading contender. Neuroimmunity however is mechanistically complex, rendering the recognition of candidate receptors a challenging task. Herein, a review of the role of neuroimmunity in the biomolecular pathogenesis of AD is presented with the identification of a 'druggable dozen' targets; in turn, each identified target represents one or more discrete receptors centred on a common biochemical mechanism. The druggable dozen is composed of both cellular and molecular messenger targets, with a 'targetable ten' microglial targets as well as two cytokine-based targets. For each target, the underlying molecular basis, with a consideration of strengths and weaknesses, is considered.
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Affiliation(s)
- Donald F Weaver
- Krembil Research Institute, University Health Network, Department of Chemistry, University of Toronto 60 Leonard Avenue Toronto ON M5T 0S8 Canada
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36
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Dutta D, Jana M, Paidi RK, Majumder M, Raha S, Dasarathy S, Pahan K. Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer's disease-related mouse models. J Clin Invest 2023; 133:e161987. [PMID: 37552543 PMCID: PMC10503811 DOI: 10.1172/jci161987] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/27/2023] [Indexed: 08/10/2023] Open
Abstract
Glial activation and inflammation coincide with neurofibrillary tangle (NFT) formation in neurons. However, the mechanism behind the interaction between tau fibrils and glia is poorly understood. Here, we found that tau preformed fibrils (PFFs) caused induction of inflammation in microglia by specifically activating the TLR2/MyD88, but not the TLR4/MyD88, pathway. Accordingly, the WT TLR2-interacting domain of MyD88 (wtTIDM) peptide inhibited tau PFF-induced activation of the TLR2/MyD88/NF-κB pathway, resulting in reduced inflammation. Nasal administration of wtTIDM in P301S tau-expressing PS19 mice was found to inhibit gliosis and inflammatory markers, as well as to reduce pathogenic tau in the hippocampus, resulting in improved cognitive behavior in PS19 mice. The inhibitory effect of wtTIDM on tau pathology was absent in PS19 mice lacking TLR2, reinforcing the essential involvement of TLR2 in wtTIDM-mediated effects in vivo. Studying the mechanism further, we found that the tau promoter harbored a potential NF-κB-binding site and that proinflammatory molecules increased transcription of tau in neurons via NF-κB. These results suggest that tau-induced neuroinflammation and neuropathology require TLR2 and that neuroinflammation directly upregulates tau in neurons via NF-κB, highlighting a direct connection between inflammation and tauopathy.
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Affiliation(s)
- Debashis Dutta
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
| | - Malabendu Jana
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
| | - Ramesh Kumar Paidi
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
| | - Moumita Majumder
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
| | - Sumita Raha
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
| | - Sridevi Dasarathy
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
| | - Kalipada Pahan
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
- Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
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Colleselli K, Stierschneider A, Wiesner C. An Update on Toll-like Receptor 2, Its Function and Dimerization in Pro- and Anti-Inflammatory Processes. Int J Mol Sci 2023; 24:12464. [PMID: 37569837 PMCID: PMC10419760 DOI: 10.3390/ijms241512464] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
While a certain level of inflammation is critical for humans to survive infection and injury, a prolonged inflammatory response can have fatal consequences. Pattern recognition Toll-like receptors (TLRs) are key players in the initiation of an inflammatory process. TLR2 is one of the most studied pattern recognition receptors (PRRs) and is known to form heterodimers with either TLR1, TLR4, TLR6, and TLR10, allowing it to recognize a wide range of pathogens. Although a large number of studies have been conducted over the past decades, there are still many unanswered questions regarding TLR2 mechanisms in health and disease. In this review, we provide an up-to-date overview of TLR2, including its homo- and heterodimers. Furthermore, we will discuss the pro- and anti-inflammatory properties of TLR2 and recent findings in prominent TLR2-associated infectious and neurodegenerative diseases.
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Affiliation(s)
| | | | - Christoph Wiesner
- Department of Medical and Pharmaceutical Biotechnology, IMC University of Applied Sciences, 3500 Krems, Austria
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Shehata MK, Ismail AA, Kamel MA. Combined Donepezil with Astaxanthin via Nanostructured Lipid Carriers Effective Delivery to Brain for Alzheimer's Disease in Rat Model. Int J Nanomedicine 2023; 18:4193-4227. [PMID: 37534058 PMCID: PMC10391537 DOI: 10.2147/ijn.s417928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/19/2023] [Indexed: 08/04/2023] Open
Abstract
Introduction Donepezil (DPL), a specific acetylcholinesterase inhibitor, is used as a first-line treatment to improve cognitive deficits in Alzheimer's disease (AD) and it might have a disease modifying effect. Astaxanthin (AST) is a natural potent antioxidant with neuroprotective, anti-amyloidogenic, anti-apoptotic, and anti-inflammatory effects. This study aimed to prepare nanostructured lipid carriers (NLCs) co-loaded with donepezil and astaxanthin (DPL/AST-NLCs) and evaluate their in vivo efficacy in an AD-like rat model 30 days after daily intranasal administration. Methods DPL/AST-NLCs were prepared using a hot high-shear homogenization technique, in vitro examined for their physicochemical parameters and in vivo evaluated. AD induction in rats was performed by aluminum chloride. The cortex and hippocampus were isolated from the brain of rats for biochemical testing and histopathological examination. Results DPL/AST-NLCs showed z-average diameter 149.9 ± 3.21 nm, polydispersity index 0.224 ± 0.017, zeta potential -33.7 ± 4.71 mV, entrapment efficiency 81.25 ±1.98% (donepezil) and 93.85 ±1.75% (astaxanthin), in vitro sustained release of both donepezil and astaxanthin for 24 h, spherical morphology by transmission electron microscopy, and they were stable at 4-8 ± 2°C for six months. Differential scanning calorimetry revealed that donepezil and astaxanthin were molecularly dispersed in the NLC matrix in an amorphous state. The DPL/AST-NLC-treated rats showed significantly lower levels of nuclear factor-kappa B, malondialdehyde, β-site amyloid precursor protein cleaving enzyme-1, caspase-3, amyloid beta (Aβ1‑42), and acetylcholinesterase, and significantly higher levels of glutathione and acetylcholine in the cortex and hippocampus than the AD-like untreated rats and that treated with donepezil-NLCs. DPL/AST-NLCs showed significantly higher anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, anti-inflammatory, and anti-apoptotic effects, resulting in significant improvement in the cortical and hippocampal histopathology. Conclusion Nose-to-brain delivery of DPL/AST-NLCs is a promising strategy for the management of AD.
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Affiliation(s)
- Mustafa K Shehata
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Assem A Ismail
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Maher A Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
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Chang JCY, Wang CY, Lin S. Interrogation of human microglial phagocytosis by CRISPR genome editing. Front Immunol 2023; 14:1169725. [PMID: 37483607 PMCID: PMC10360658 DOI: 10.3389/fimmu.2023.1169725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/23/2023] [Indexed: 07/25/2023] Open
Abstract
Background Microglia are an integral part of central nervous system, but our understanding of microglial biology is limited due to the challenges in obtaining and culturing primary human microglia. HMC3 is an important cell line for studying human microglia because it is readily accessible and straightforward to maintain in standard laboratories. Although HMC3 is widely used for microglial research, a robust genetic method has not been described. Here, we report a CRISPR genome editing platform, by the electroporation of Cas9 ribonucleoproteins (Cas9 RNP) and synthetic DNA repair templates, to enable rapid and precise genetic modifications of HMC3. For proof-of-concept demonstrations, we targeted the genes implicated in the regulation of amyloid beta (Aβ) and glioblastoma phagocytosis in microglia. We showed that CRISPR genome editing could enhance the phagocytic activities of HMC3. Methods We performed CRISPR gene knockout (KO) in HMC3 by the electroporation of pre-assembled Cas9 RNP. Co-introduction of DNA repair templates allowed site-specific knock-in (KI) of an epitope tag, a synthetic promoter and a fluorescent reporter gene. The editing efficiencies were determined genotypically by DNA sequencing and phenotypically by immunofluorescent staining and flow cytometry. The gene-edited HMC3 cells were examined in vitro by fluorescent Aβ and glioblastoma phagocytosis assays. Results Our platform enabled robust single (>90%) and double (>70%) KO without detectable off-target editing by high throughput DNA sequencing. We also inserted a synthetic SFFV promoter to efficiently upregulate the expression of endogenous CD14 and TREM2 genes associated with microglial phagocytosis. The CRISPR-edited HMC3 showed stable phenotypes and enhanced phagocytosis of fluorescence-labeled Aβ1-42 peptides. Confocal microscopy further confirmed the localization of Aβ1-42 aggregates in the acidified lysosomes. HMC3 mutants also changed the phagocytic characteristic toward apoptotic glioblastoma cells. Conclusion CRISPR genome editing by Cas9 RNP electroporation is a robust approach to genetically modify HMC3 for functional studies such as the interrogation of Aβ and tumor phagocytosis, and is readily adoptable to investigate other aspects of microglial biology.
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Affiliation(s)
| | - Cheng-You Wang
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Steven Lin
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
- Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
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Hnath B, Chen J, Reynolds J, Choi E, Wang J, Zhang D, Sha CM, Dokholyan NV. Big versus small: The impact of aggregate size in disease. Protein Sci 2023; 32:e4686. [PMID: 37243896 PMCID: PMC10273386 DOI: 10.1002/pro.4686] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/17/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023]
Abstract
Protein aggregation results in an array of different size soluble oligomers and larger insoluble fibrils. Insoluble fibrils were originally thought to cause neuronal cell deaths in neurodegenerative diseases due to their prevalence in tissue samples and disease models. Despite recent studies demonstrating the toxicity associated with soluble oligomers, many therapeutic strategies still focus on fibrils or consider all types of aggregates as one group. Oligomers and fibrils require different modeling and therapeutic strategies, targeting the toxic species is crucial for successful study and therapeutic development. Here, we review the role of different-size aggregates in disease, and how factors contributing to aggregation (mutations, metals, post-translational modifications, and lipid interactions) may promote oligomers opposed to fibrils. We review two different computational modeling strategies (molecular dynamics and kinetic modeling) and how they are used to model both oligomers and fibrils. Finally, we outline the current therapeutic strategies targeting aggregating proteins and their strengths and weaknesses for targeting oligomers versus fibrils. Altogether, we aim to highlight the importance of distinguishing the difference between oligomers and fibrils and determining which species is toxic when modeling and creating therapeutics for protein aggregation in disease.
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Affiliation(s)
- Brianna Hnath
- Department of Biomedical EngineeringPenn State UniversityUniversity ParkPennsylvaniaUSA
- Department of PharmacologyPenn State College of MedicineHersheyPennsylvaniaUSA
| | - Jiaxing Chen
- Department of PharmacologyPenn State College of MedicineHersheyPennsylvaniaUSA
| | - Joshua Reynolds
- Department of Biomedical EngineeringPenn State UniversityUniversity ParkPennsylvaniaUSA
- Department of PharmacologyPenn State College of MedicineHersheyPennsylvaniaUSA
| | - Esther Choi
- Department of PharmacologyPenn State College of MedicineHersheyPennsylvaniaUSA
- Medical Scientist Training ProgramPenn State College of MedicineHersheyPennsylvaniaUSA
| | - Jian Wang
- Department of PharmacologyPenn State College of MedicineHersheyPennsylvaniaUSA
| | - Dongyan Zhang
- Department of PharmacologyPenn State College of MedicineHersheyPennsylvaniaUSA
| | - Congzhou M. Sha
- Department of PharmacologyPenn State College of MedicineHersheyPennsylvaniaUSA
- Medical Scientist Training ProgramPenn State College of MedicineHersheyPennsylvaniaUSA
- Department of Engineering Science and MechanicsPenn State UniversityUniversity ParkPennsylvaniaUSA
| | - Nikolay V. Dokholyan
- Department of Biomedical EngineeringPenn State UniversityUniversity ParkPennsylvaniaUSA
- Department of PharmacologyPenn State College of MedicineHersheyPennsylvaniaUSA
- Department of Engineering Science and MechanicsPenn State UniversityUniversity ParkPennsylvaniaUSA
- Department of Biochemistry & Molecular BiologyPenn State College of MedicineHersheyPennsylvaniaUSA
- Department of ChemistryPenn State UniversityUniversity ParkPennsylvaniaUSA
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Miao J, Ma H, Yang Y, Liao Y, Lin C, Zheng J, Yu M, Lan J. Microglia in Alzheimer's disease: pathogenesis, mechanisms, and therapeutic potentials. Front Aging Neurosci 2023; 15:1201982. [PMID: 37396657 PMCID: PMC10309009 DOI: 10.3389/fnagi.2023.1201982] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 05/30/2023] [Indexed: 07/04/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by protein aggregation in the brain. Recent studies have revealed the critical role of microglia in AD pathogenesis. This review provides a comprehensive summary of the current understanding of microglial involvement in AD, focusing on genetic determinants, phenotypic state, phagocytic capacity, neuroinflammatory response, and impact on synaptic plasticity and neuronal regulation. Furthermore, recent developments in drug discovery targeting microglia in AD are reviewed, highlighting potential avenues for therapeutic intervention. This review emphasizes the essential role of microglia in AD and provides insights into potential treatments.
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Affiliation(s)
- Jifei Miao
- Shenzhen Bao’an Traditional Chinese Medicine Hospital, Shenzhen, China
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Haixia Ma
- Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yang Yang
- Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yuanpin Liao
- Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Cui Lin
- Shenzhen Bao’an Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Juanxia Zheng
- Shenzhen Bao’an Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Muli Yu
- Shenzhen Bao’an Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Jiao Lan
- Shenzhen Bao’an Traditional Chinese Medicine Hospital, Shenzhen, China
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Almarhoumi R, Alvarez C, Harris T, Tognoni CM, Paster BJ, Carreras I, Dedeoglu A, Kantarci A. Microglial cell response to experimental periodontal disease. J Neuroinflammation 2023; 20:142. [PMID: 37316834 PMCID: PMC10265806 DOI: 10.1186/s12974-023-02821-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/29/2023] [Indexed: 06/16/2023] Open
Abstract
OBJECTIVES Microglial activation is critical for modulating the neuroinflammatory process and the pathological progression of neurodegenerative diseases, such as Alzheimer's disease (AD). Microglia are involved in forming barriers around extracellular neuritic plaques and the phagocytosis of β-amyloid peptide (Aβ). In this study, we tested the hypothesis that periodontal disease (PD) as a source of infection alters inflammatory activation and Aβ phagocytosis by the microglial cells. METHODS Experimental PD was induced using ligatures in C57BL/6 mice for 1, 10, 20, and 30 days to assess the progression of PD. Animals without ligatures were used as controls. Maxillary bone loss and local periodontal tissue inflammation associated with the development of PD were confirmed by morphometric bone analysis and cytokine expression, respectively. The frequency and the total number of activated microglia (CD45+ CD11b+ MHCII+) in the brain were analyzed by flow cytometry. Mouse microglial cells (1 × 105) were incubated with heat-inactivated bacterial biofilm isolated from the ligatures retrieved from the teeth or with Klebsiella variicola, a relevant PD-associated bacteria in mice. Expression of pro-inflammatory cytokines, toll-like receptors (TLR), and receptors for phagocytosis was measured by quantitative PCR. The phagocytic capacity of microglia to uptake β-amyloid was analyzed by flow cytometry. RESULTS Ligature placement caused progressive periodontal disease and bone resorption that was already significant on day 1 post-ligation (p < 0.05) and continued to increase until day 30 (p < 0.0001). The severity of periodontal disease increased the frequency of activated microglia in the brains on day 30 by 36%. In parallel, heat-inactivated PD-associated total bacteria and Klebsiella variicola increased the expression of TNFα, IL-1β, IL-6, TLR2, and TLR9 in microglial cells (1.6-, 83-, 3.2-, 1.5-, 1.5-fold, respectively p < 0.01). Incubation of microglia with Klebsiella variicola increased the Aβ-phagocytosis by 394% and the expression of the phagocytic receptor MSR1 by 33-fold compared to the non-activated cells (p < 0.0001). CONCLUSIONS We showed that inducing PD in mice results in microglia activation in vivo and that PD-associated bacteria directly promote a pro-inflammatory and phagocytic phenotype in microglia. These results support a direct role of PD-associated pathogens in neuroinflammation.
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Affiliation(s)
- Rawan Almarhoumi
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 USA
- Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Carla Alvarez
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 USA
| | - Theodore Harris
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
| | - Christina M. Tognoni
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA 02130 USA
- Department of Neurology, Boston University School of Medicine, Boston, MA 02118 USA
| | - Bruce J. Paster
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 USA
| | - Isabel Carreras
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA 02130 USA
- Department of Neurology, Boston University School of Medicine, Boston, MA 02118 USA
- Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118 USA
| | - Alpaslan Dedeoglu
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA 02130 USA
- Department of Neurology, Boston University School of Medicine, Boston, MA 02118 USA
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA
| | - Alpdogan Kantarci
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 USA
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Wątroba M, Grabowska AD, Szukiewicz D. Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood-Brain Barrier and the Risk of Dementia. Int J Mol Sci 2023; 24:10069. [PMID: 37373216 DOI: 10.3390/ijms241210069] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.
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Affiliation(s)
- Mateusz Wątroba
- Laboratory of the Blood-Brain Barrier, Department of Biophysics, Physiology & Pathophysiology, Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland
| | - Anna D Grabowska
- Laboratory of the Blood-Brain Barrier, Department of Biophysics, Physiology & Pathophysiology, Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland
| | - Dariusz Szukiewicz
- Laboratory of the Blood-Brain Barrier, Department of Biophysics, Physiology & Pathophysiology, Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland
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Coppin E, Zhang X, Ohayon L, Johny E, Dasari A, Zheng KH, Stiekema L, Cifuentes-Pagano E, Pagano PJ, Chaparala S, Stroes ES, Dutta P. Peripheral Ischemia Imprints Epigenetic Changes in Hematopoietic Stem Cells to Propagate Inflammation and Atherosclerosis. Arterioscler Thromb Vasc Biol 2023; 43:889-906. [PMID: 36891902 PMCID: PMC10213134 DOI: 10.1161/atvbaha.123.318956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 02/20/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND Peripheral ischemia caused by peripheral artery disease is associated with systemic inflammation, which may aggravate underlying comorbidities such as atherosclerosis and heart failure. However, the mechanisms of increased inflammation and inflammatory cell production in patients with peripheral artery disease remain poorly understood. METHODS We used peripheral blood collected from patients with peripheral artery disease and performed hind limb ischemia (HI) in Apoe-/- mice fed a Western diet and C57BL/6J mice with a standard laboratory diet. Bulk and single-cell RNA sequencing analysis, whole-mount microscopy, and flow cytometry were performed to analyze hematopoietic stem and progenitor cell (HSPC) proliferation, differentiation, and relocation. RESULTS We observed augmented numbers of leukocytes in the blood of patients with peripheral artery disease and Apoe-/- mice with HI. RNA sequencing and whole-mount imaging of the bone marrow revealed HSPC migration into the vascular niche from the osteoblastic niche and their exaggerated proliferation and differentiation. Single-cell RNA sequencing demonstrated alterations in the genes responsible for inflammation, myeloid cell mobilization, and HSPC differentiation after HI. Heightened inflammation in Apoe-/- mice after HI aggravated atherosclerosis. Surprisingly, bone marrow HSPCs expressed higher amounts of the receptors for IL (interleukin)-1 and IL-3 after HI. Concomitantly, the promoters of Il1r1 and Il3rb had augmented H3K4me3 and H3K27ac marks after HI. Genetic and pharmacological inhibition of these receptors resulted in suppressed HSPC proliferation, reduced leukocyte production, and ameliorated atherosclerosis. CONCLUSIONS Our findings demonstrate increased inflammation, HSPC abundance in the vascular niches of the bone marrow, and elevated IL-3Rb and IL-1R1 (IL-1 receptor 1) expression in HSPC following HI. Furthermore, the IL-3Rb and IL-1R1 signaling plays a pivotal role in HSPC proliferation, leukocyte abundance, and atherosclerosis aggravation after HI.
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Affiliation(s)
- Emilie Coppin
- Regeneration in Hematopoiesis, Institute for Immunology, TU Dresden, Dresden, Germany
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Xinyi Zhang
- Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Lee Ohayon
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Ebin Johny
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Ankush Dasari
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Kang H. Zheng
- Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Lotte Stiekema
- Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Eugenia Cifuentes-Pagano
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Patrick J. Pagano
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Srilakshmi Chaparala
- Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Erik S. Stroes
- Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Partha Dutta
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh VA Medical Center-University Drive, University Drive C, Pittsburgh, PA, 15213
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Braun DJ, Frazier HN, Davis VA, Coleman MJ, Rogers CB, Van Eldik LJ. Early chronic suppression of microglial p38α in a model of Alzheimer's disease does not significantly alter amyloid-associated neuropathology. PLoS One 2023; 18:e0286495. [PMID: 37256881 PMCID: PMC10231773 DOI: 10.1371/journal.pone.0286495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/17/2023] [Indexed: 06/02/2023] Open
Abstract
The p38 alpha mitogen-activated protein kinase (p38α) is linked to both innate and adaptive immune responses and is under investigation as a target for drug development in the context of Alzheimer's disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38α inhibition can protect against AD-associated neuropathology, the underlying mechanisms are not fully elucidated. Inhibitors of p38α may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to AD pathology. The present study tests this hypothesis by knocking out microglial p38α and assessing early-stage pathological changes. Conditional knockout of microglial p38α was accomplished in 5-month-old C57BL/6J wild-type and amyloidogenic AD model (APPswe/PS1dE9) mice using a tamoxifen-inducible Cre/loxP system under control of the Cx3cr1 promoter. Beginning at 7.5 months of age, animals underwent behavioral assessment on the open field, followed by a later radial arm water maze test and collection of cortical and hippocampal tissues at 11 months. Additional endpoint measures included quantification of proinflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia-plaque dynamics. Loss of microglial p38α did not alter behavioral outcomes, proinflammatory cytokine levels, or overall amyloid plaque burden. However, this manipulation did significantly increase hippocampal levels of soluble Aβ42 and reduce colocalization of Iba1 and 6E10 in a subset of microglia in close proximity to plaques. The data presented here suggest that rather than reducing inflammation per se, the net effect of microglial p38α inhibition in the context of early AD-type amyloid pathology is a subtle alteration of microglia-plaque interactions. Encouragingly from a therapeutic standpoint, these data suggest no detrimental effect of even substantial decreases in microglial p38α in this context. Additionally, these results support future investigations of microglial p38α signaling at different stages of disease, as well as its relationship to phagocytic processes in this particular cell-type.
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Affiliation(s)
- David J. Braun
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky, United States of America
| | - Hilaree N. Frazier
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America
| | - Verda A. Davis
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America
| | - Meggie J. Coleman
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America
| | - Colin B. Rogers
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America
| | - Linda J. Van Eldik
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky, United States of America
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Thu VTA, Hoang TX, Kim JY. 1,25-Dihydroxy Vitamin D 3 Facilitates the M2 Polarization and β-Amyloid Uptake by Human Microglia in a TREM2-Dependent Manner. BIOMED RESEARCH INTERNATIONAL 2023; 2023:3483411. [PMID: 37274074 PMCID: PMC10239306 DOI: 10.1155/2023/3483411] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/23/2023] [Accepted: 05/17/2023] [Indexed: 06/06/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia as the primary clinical symptom. The production and accumulation of aggregated β-amyloid (Aβ) in patient brain tissues is one of the hallmarks of AD pathogenesis. Microglia, brain-resident macrophages, produce inflammatory cytokines in response to Aβ oligomers or fibrils exacerbating Aβ pathology in AD. HMO6 cells were treated with Aβ42 in the presence or absence of 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) to determine its potential immunomodulatory effects, and the expression of pro-/anti-inflammatory cytokines, M1/M2-associated markers, Toll-like receptors (TLRs), and triggering receptor expressed on myeloid cells 2 (TREM2) was examined. 1,25(OH)2D3 was found to suppress Aβ-induced expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), M1 markers (CD86 and iNOS), and TLR2/4, whilst increasing the expression of anti-inflammatory cytokines (IL-4, IL-10, and CCL17) and M2 markers (CD206 and Arg-1). Furthermore, 1,25(OH)2D3 promoted TREM2 expression and Aβ uptake by HMO6 cells, and the enhancement of Aβ uptake and M2 polarization was revealed to be TREM2-dependent. The findings of this study suggest that 1,25(OH)2D3 facilitates M2 polarization and Aβ uptake in a TREM2-dependent manner.
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Affiliation(s)
- Vo Thuy Anh Thu
- Department of Life Science, Gachon University, Seongnam, Gyeonggi-do 13120, Republic of Korea
| | - Thi Xoan Hoang
- Department of Life Science, Gachon University, Seongnam, Gyeonggi-do 13120, Republic of Korea
| | - Jae Young Kim
- Department of Life Science, Gachon University, Seongnam, Gyeonggi-do 13120, Republic of Korea
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Pearson A, Ortiz C, Eisenbaum M, Arrate C, Browning M, Mullan M, Bachmeier C, Crawford F, Ojo JO. Deletion of PTEN in microglia ameliorates chronic neuroinflammation following repetitive mTBI. Mol Cell Neurosci 2023; 125:103855. [PMID: 37084991 DOI: 10.1016/j.mcn.2023.103855] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 03/25/2023] [Accepted: 04/17/2023] [Indexed: 04/23/2023] Open
Abstract
Traumatic brain injury is a leading cause of morbidity and mortality in adults and children in developed nations. Following the primary injury, microglia, the resident innate immune cells of the CNS, initiate several inflammatory signaling cascades and pathophysiological responses that may persist chronically; chronic neuroinflammation following TBI has been closely linked to the development of neurodegeneration and neurological dysfunction. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been shown to regulate several key mechanisms in the inflammatory response to TBI. Increasing evidence has shown that the modulation of the PI3K/AKT signaling pathway has the potential to influence the cellular response to inflammatory stimuli. However, directly targeting PI3K signaling poses several challenges due to its regulatory role in several cell survival pathways. We have previously identified that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), the major negative regulator of PI3K/AKT signaling, is dysregulated following exposure to repetitive mild traumatic brain injury (r-mTBI). Moreover, this dysregulated PI3K/AKT signaling was correlated with chronic microglial-mediated neuroinflammation. Therefore, we interrogated microglial-specific PTEN as a therapeutic target in TBI by generating a microglial-specific, Tamoxifen inducible conditional PTEN knockout model using a CX3CR1 Cre recombinase mouse line PTENfl/fl/CX3CR1+/CreERT2 (mcg-PTENcKO), and exposed them to our 20-hit r-mTBI paradigm. Animals were treated with tamoxifen at 76 days post-last injury, and the effects of microglia PTEN deletion on immune-inflammatory responses were assessed at 90-days post last injury. We observed that the deletion of microglial PTEN ameliorated the proinflammatory response to repetitive brain trauma, not only reducing chronic microglial activation and proinflammatory cytokine production but also rescuing TBI-induced reactive astrogliosis, demonstrating that these effects extended beyond microglia alone. Additionally, we observed that the pharmacological inhibition of PTEN with BpV(HOpic) ameliorated the LPS-induced activation of microglial NFκB signaling in vitro. Together, these data provide support for the role of PTEN as a regulator of chronic neuroinflammation following repetitive mild TBI.
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Affiliation(s)
- Andrew Pearson
- The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA; The Open University, Walton Hall, Kents Hill, Milton Keynes MK7 6AA, United Kingdom.
| | - Camila Ortiz
- The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA; The Open University, Walton Hall, Kents Hill, Milton Keynes MK7 6AA, United Kingdom
| | - Max Eisenbaum
- The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA; The Open University, Walton Hall, Kents Hill, Milton Keynes MK7 6AA, United Kingdom
| | - Clara Arrate
- The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA
| | | | - Michael Mullan
- The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA; The Open University, Walton Hall, Kents Hill, Milton Keynes MK7 6AA, United Kingdom
| | - Corbin Bachmeier
- The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA; The Open University, Walton Hall, Kents Hill, Milton Keynes MK7 6AA, United Kingdom
| | - Fiona Crawford
- The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA; The Open University, Walton Hall, Kents Hill, Milton Keynes MK7 6AA, United Kingdom; James A. Haley Veterans' Hospital, 13000 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Joseph O Ojo
- The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA; The Open University, Walton Hall, Kents Hill, Milton Keynes MK7 6AA, United Kingdom
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Afsar A, Chacon Castro MDC, Soladogun AS, Zhang L. Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer's Disease. Int J Mol Sci 2023; 24:7258. [PMID: 37108421 PMCID: PMC10138573 DOI: 10.3390/ijms24087258] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/22/2023] [Accepted: 03/28/2023] [Indexed: 04/29/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood-brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.
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Affiliation(s)
| | | | | | - Li Zhang
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA
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Poppell M, Hammel G, Ren Y. Immune Regulatory Functions of Macrophages and Microglia in Central Nervous System Diseases. Int J Mol Sci 2023; 24:5925. [PMID: 36982999 PMCID: PMC10059890 DOI: 10.3390/ijms24065925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/08/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
Macrophages can be characterized as a very multifunctional cell type with a spectrum of phenotypes and functions being observed spatially and temporally in various disease states. Ample studies have now demonstrated a possible causal link between macrophage activation and the development of autoimmune disorders. How these cells may be contributing to the adaptive immune response and potentially perpetuating the progression of neurodegenerative diseases and neural injuries is not fully understood. Within this review, we hope to illustrate the role that macrophages and microglia play as initiators of adaptive immune response in various CNS diseases by offering evidence of: (1) the types of immune responses and the processes of antigen presentation in each disease, (2) receptors involved in macrophage/microglial phagocytosis of disease-related cell debris or molecules, and, finally, (3) the implications of macrophages/microglia on the pathogenesis of the diseases.
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Affiliation(s)
| | | | - Yi Ren
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
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Chang J, Qian Z, Wang B, Cao J, Zhang S, Jiang F, Kong R, Yu X, Cao X, Yang L, Chen H. Transplantation of A2 type astrocytes promotes neural repair and remyelination after spinal cord injury. Cell Commun Signal 2023; 21:37. [PMID: 36797790 PMCID: PMC9936716 DOI: 10.1186/s12964-022-01036-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 12/28/2022] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND Limited progress in terms of an effective treatment for spinal cord injury (SCI) emphasizes the urgent need for novel therapies. As a vital central nervous system component, the resident astrocytes play crucial roles in regulating recovery after SCI. In this study, recovery after SCI was compared following the transplantation of either A1 or A2 astrocytes. A1 astrocytes are harmful as they upregulate the neurotoxic classical complement cascade genes. Conversely, A2 astrocytes are characterized as neuroprotective as they upregulate the production of many neurotrophic factors. METHODS We used different supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4 to generate A1 and A2 astrocytes. We detected the influence of astrocytes on neurons by co-culturing A1 and A2 astrocytes with neurons. We transplanted astrocytes into the lesion site of the spinal cord and assessed lesion progression, neural restoration, glia formation and locomotor recovery. RESULTS Astrocytes were polarized into A1 and A2 phenotypes following culture in the supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4, respectively. Furthermore, co-culturing A2 astrocytes with neurons significantly suppressed glutamate-induced neuronal apoptosis and promoted the degree of neuron arborization. Transplantation of these A2 astrocytes into the lesion site of the spinal cord of mice significantly improved motor function recovery, preserved spared supraspinal pathways, decreased glia scar deposition, and increased neurofilament formation at the site of injury compared to the transplantation of A1 astrocytes. Additionally, enhanced A2 astrocytes with potentially beneficial A2-like genes were also detected in the A2 group. Moreover, luxol fast blue staining and electron microscopy indicated increased preservation of myelin with organized structure after transplantation of A2 astrocytes than of A1 astrocytes. CONCLUSIONS A2 astrocyte transplantation could be a promising potential therapy for SCI. Video abstract.
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Affiliation(s)
- Jie Chang
- Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.,Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Zhanyang Qian
- Spine Center, Zhongda Hospital of Southeast University, Nanjing, Jiangsu, China
| | - Binyu Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Jiang Cao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Sheng Zhang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Fan Jiang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Renyi Kong
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Xiao Yu
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Xiaojian Cao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Lei Yang
- Department of Orthopedics, Taizhou People's Hospital, Nanjing Medical University, No. 366 Taihu Road, Taizhou, 225300, Jiangsu, China. .,School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Hongtao Chen
- Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
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