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Guo J, Zhu Y, Zhi J, Lou Q, Bai R, He Y. Antioxidants in anti-Alzheimer's disease drug discovery. Ageing Res Rev 2025; 107:102707. [PMID: 40021094 DOI: 10.1016/j.arr.2025.102707] [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: 01/15/2025] [Revised: 02/17/2025] [Accepted: 02/21/2025] [Indexed: 03/03/2025]
Abstract
Oxidative stress is widely recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). While not the sole factor, it is closely linked to critical pathological features, such as the formation of senile plaques and neurofibrillary tangles. The development of agents with antioxidant properties has become an area of growing interest in AD research. Between 2015 and 2024, several antioxidant-targeted drugs for AD progressed to clinical trials, with increasing attention to the evaluation of antioxidant properties during their development. Oxidative stress plays a pivotal role in linking various AD hypotheses, underscoring its importance in understanding the disease mechanisms. Despite this, comprehensive reviews addressing advancements in AD drug development from the perspective of antioxidant capacity remain limited, hindering the design of novel compounds. This review aims to explore the mechanistic relationship between oxidative stress and AD, summarize methods for assessing antioxidant capacity, and provide an overview of antioxidant compounds with anti-AD properties reported over the past decade. The goal is to offer strategies for identifying effective antioxidant-based therapies for AD and to deepen our understanding of the role of oxidative stress in AD pathology.
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Affiliation(s)
- Jianan Guo
- Department of Pharmacy, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province 321000, PR China; Central Laboratory and Precision Medicine Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province 321000, PR China; Jinhua Key Laboratory of Cancer Nutrition and Metabolism Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province 321000, PR China.
| | - Yalan Zhu
- Department of Pharmacy, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province 321000, PR China
| | - Jia Zhi
- Department of Medicinal Chemistry, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Qiuwen Lou
- Central Laboratory and Precision Medicine Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province 321000, PR China; Jinhua Key Laboratory of Cancer Nutrition and Metabolism Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province 321000, PR China
| | - Renren Bai
- Department of Medicinal Chemistry, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China.
| | - Yiling He
- Department of Pharmacy, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province 321000, PR China.
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Kulkarni R, Kumari S, Dhapola R, Sharma P, Singh SK, Medhi B, HariKrishnaReddy D. Association Between the Gut Microbiota and Alzheimer's Disease: An Update on Signaling Pathways and Translational Therapeutics. Mol Neurobiol 2025; 62:4499-4519. [PMID: 39460901 DOI: 10.1007/s12035-024-04545-2] [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: 05/06/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024]
Abstract
Alzheimer's disease (AD) is a cognitive disease with high morbidity and mortality. In AD patients, the diversity of the gut microbiota is altered, which influences pathology through the gut-brain axis. Probiotic therapy alleviates pathological and psychological consequences by restoring the diversity of the gut microbial flora. This study addresses the role of altered gut microbiota in the progression of neuroinflammation, which is a major hallmark of AD. This process begins with the activation of glial cells, leading to the release of proinflammatory cytokines and the modulation of cholinergic anti-inflammatory pathways. Short-chain fatty acids, which are bacterial metabolites, provide neuroprotective effects and maintain blood‒brain barrier integrity. Furthermore, the gut microbiota stimulates oxidative stress and mitochondrial dysfunction, which promote AD progression. The signaling pathways involved in gut dysbiosis-mediated neuroinflammation-mediated promotion of AD include cGAS-STING, C/EBPβ/AEP, RAGE, TLR4 Myd88, and the NLRP3 inflammasome. Preclinical studies have shown that natural extracts such as Ganmaidazao extract, isoorentin, camelia oil, Sparassis crispa-1, and xanthocerasides improve gut health and can delay the worsening of AD. Clinical studies using probiotics such as Bifidobacterium spp., yeast beta-glucan, and drugs such as sodium oligomannate and rifaximine have shown improvements in gut health, resulting in the amelioration of AD symptoms. This study incorporates the most current research on the pathophysiology of AD involving the gut microbiota and highlights the knowledge gaps that need to be filled to develop potent therapeutics against AD.
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Affiliation(s)
- Rutweek Kulkarni
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda, 151401, Punjab, India
| | - Sneha Kumari
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda, 151401, Punjab, India
| | - Rishika Dhapola
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda, 151401, Punjab, India
| | - Prajjwal Sharma
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda, 151401, Punjab, India
| | - Sunil K Singh
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Bikash Medhi
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Dibbanti HariKrishnaReddy
- Advanced Pharmacology and Neuroscience Laboratory, Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda, 151401, Punjab, India.
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Zhang Y, Wang Y, Wang H, Bian L, Gao F, Yao H, Xie J. Intranasal Delivery of Hydrophobic AC5216 Loaded Nanoemulsion into Brain To Alleviate Chronic Unpredictable Stress-Induced Depressive-like Behaviors. ACS APPLIED MATERIALS & INTERFACES 2025; 17:16533-16547. [PMID: 40063900 DOI: 10.1021/acsami.4c19377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/21/2025]
Abstract
Major depressive disorder (MDD) represents a widespread mental health condition. Efficiently moving therapeutic substances across the blood-brain barrier (BBB) remains a critical obstacle in addressing depressive disorders. AC5216, identified as a translocator protein (TSPO) ligand and considered a potential treatment for major depressive disorder (MDD), faces limitations due to its subpar druggability and oral bioavailability. In this context, an amphiphilic polymer composed of polyethylene glycol, poly-l-lysine, and poly(lactic-co-glycolic acid) (PEG-PLL-PLGA) has been utilized to encapsulate the hydrophobic compound AC5216. This results in the formation of cell-penetrating peptide-modified nanoemulsions (termed CPP-PPP-AC5216), designed to deliver AC5216 directly into the central nervous system via intranasal administration for MDD therapy. Research on animal models has shown that CPP-PPP-AC5216 effectively transports AC5216 to the brain, significantly mitigating chronic unpredictable stress (CUS)-induced depressive behaviors with a dosage as low as 0.03 mg/kg when administered intranasally. Furthermore, it was observed that CPP-PPP-AC5216 substantially reduces microglial activation, prevents BBB leakage, and ameliorates astrocyte dysfunction caused by CUS. The findings suggest a promising potential for using this nanoemulsion approach to deliver hydrophobic compounds through the nasal route for the treatment of MDD.
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Affiliation(s)
- Yuan Zhang
- Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing 210009, China
| | - Yuqi Wang
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Basic Medicine Research and Innovation Center of Ministry of Education, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Huijuan Wang
- Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing 210009, China
| | - Liang Bian
- Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing 210009, China
| | - Feng Gao
- Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing 210009, China
| | - Honghong Yao
- Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing 210009, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China
- Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210009, China
| | - Jinbing Xie
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Basic Medicine Research and Innovation Center of Ministry of Education, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
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Tang S, Zhang Y, Botchway BOA, Wang X, Huang M, Liu X. Epigallocatechin-3-Gallate Inhibits Oxidative Stress Through the Keap1/Nrf2 Signaling Pathway to Improve Alzheimer Disease. Mol Neurobiol 2025; 62:3493-3507. [PMID: 39299981 DOI: 10.1007/s12035-024-04498-6] [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: 04/23/2024] [Accepted: 09/12/2024] [Indexed: 09/22/2024]
Abstract
Alzheimer disease (AD) is a common neurodegenerative disease with an intricate pathophysiological mechanism. Oxidative stress has been shown in several investigations as a significant factor in AD progression. For instance, studies have confirmed that oxidative stress inhibition may considerably improve AD symptoms, with potent antioxidants being touted as a possible interventional strategy in the search for AD treatment. Epigallocatechin-3-gallate (EGCG) acts as a natural catechin that has antioxidant effect. It activates the kelch-like epichlorohydrin-associated proteins (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway to inhibit oxidative stress. The Keap1/Nrf2 signal pathway is not only an upstream signaling target for a variety of antioxidant enzymes, but also minimizes high levels of reactive oxygen species. This report analyzes the antioxidant effect of EGCG in AD, elaborates its specific mechanism of action, and provides a theoretical basis for its clinical application in AD.
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Affiliation(s)
- Shi Tang
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Shaoxing, 312000, China
| | - Yong Zhang
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Shaoxing, 312000, China
| | - Benson O A Botchway
- Bupa Cromwell Hospital, Kensington, London, UK
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus
| | - Xichen Wang
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Shaoxing, 312000, China
| | - Min Huang
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Shaoxing, 312000, China
| | - Xuehong Liu
- Department of Histology and Embryology, School of Medicine, Shaoxing University, Shaoxing, 312000, China.
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Chen J, Zhu Z, Xu F, Dou B, Sheng Z, Xu Y. Phosphodiesterase 4 Inhibition in Neuropsychiatric Disorders Associated with Alzheimer's Disease. Cells 2025; 14:164. [PMID: 39936956 PMCID: PMC11816594 DOI: 10.3390/cells14030164] [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: 11/10/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 02/13/2025] Open
Abstract
Cognitive disorders and psychiatric pathologies, particularly Alzheimer's disease (AD) and Major depressive disorder (MDD), represent a considerable health burden, impacting millions of people in the United States and worldwide. Notably, comorbidities of MDD and anxiety are prevalent in the early stages of mild cognitive impairment (MCI), which is the preceding phase of Alzheimer's disease and related dementia (ADRD). The symptoms of MDD and anxiety affect up to 80% of individuals in the advanced stages of the neurodegenerative conditions. Despite overlapping clinical manifestations, the pathogenesis of AD/ADRD and MDD remains inadequately elucidated. Until now, dozens of drugs for treating AD/ADRD have failed in clinical trials because they have not proven beneficial in reversing or preventing the progression of these neuropsychiatric indications. This underscores the need to identify new drug targets that could reverse neuropsychiatric symptoms and delay the progress of AD/ADRD. In this context, phosphodiesterase 4 (PDE4) arises as a primary enzyme in the modulation of cognition and mood disorders, particularly through its enzymatic action on cyclic adenosine monophosphate (cAMP) and its downstream anti-inflammatory pathways. Despite the considerable cognitive and antidepressant potential of PDE4 inhibitors, their translation into clinical practice is hampered by profound side effects. Recent studies have focused on the effects of PDE4 and its subtype-selective isoform inhibitors, aiming to delineate their precise mechanistic contributions to neuropsychiatric symptoms with greater specificity. This review aims to analyze the current advances regarding PDE4 inhibition-specifically the selective targeting of its isoforms and elucidate the therapeutic implications of enhanced cAMP signaling and the consequent anti-inflammatory responses in ameliorating the symptomatology associated with AD and ADRD.
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Affiliation(s)
- Jiming Chen
- Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; (J.C.); (F.X.); (B.D.); (Z.S.)
| | - Zhengyao Zhu
- School of Nursing and Rehabilitation, Nantong University, Nantong 226007, China;
| | - Fu Xu
- Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; (J.C.); (F.X.); (B.D.); (Z.S.)
| | - Baomin Dou
- Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; (J.C.); (F.X.); (B.D.); (Z.S.)
| | - Zhutao Sheng
- Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; (J.C.); (F.X.); (B.D.); (Z.S.)
| | - Ying Xu
- Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; (J.C.); (F.X.); (B.D.); (Z.S.)
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Xing X, Liu H, Zhang M, Li Y. Mapping the current trends and hotspots of extracellular vesicles in Alzheimer's disease: a bibliometric analysis. Front Aging Neurosci 2024; 16:1485750. [PMID: 39759397 PMCID: PMC11697149 DOI: 10.3389/fnagi.2024.1485750] [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: 08/24/2024] [Accepted: 12/06/2024] [Indexed: 01/07/2025] Open
Abstract
Background Extracellular vesicles (EVs) have garnered significant attention in Alzheimer's disease (AD) research over the past decade, largely due to their potential in diagnostics and therapeutics. Although the investigation of EVs in AD is a relatively recent endeavor, a comprehensive bibliometric analysis of this rapidly growing field has yet to be conducted. Methods This study aims to elucidate and synthesize the relationship between EVs and AD, offering critical insights to guide future research and expand therapeutic possibilities. Over the past 10-15 years, substantial progress has been made in this domain. Through bibliometric techniques, this analysis assesses research performance by examining scientific publications and metrics, including productivity indicators, impact measurements, data mining, and visualization tools. Results A total of 602 publications were analyzed using various online platforms for bibliometric analysis. Notably, the number of publications began to increase rapidly in 2018, with China and the United States emerging as leaders in this research area. The National Institute on Aging produced the highest number of publications among institutions. The Journal of Molecular Sciences and the Journal of Biological Chemistry were the most prolific and most frequently cited journals, respectively. Among individual contributors, Dimitrios Kapogiannis was identified as the most productive author, while Edward J. Goetzl was the most co-cited. The most prevalent keywords included "neurodegenerative diseases," "exosomes," "blood biomarkers," "amyloid beta," "microglia," and "tau protein." Current research hotspots involve microRNA dysregulation, oxidative stress, carboxyl-terminal fragments, small EVs, and mesenchymal stem cell-derived EVs, indicating key areas for future research. Conclusion Research on microRNA dysregulation, oxidative stress, carboxyl-terminal fragments, small EVs, and mesenchymal stem cell-derived EVs represents a critical frontier in the study of Alzheimer's disease. The role of EV-mediated neuroinflammation in AD is a focal point of ongoing investigation and will likely shape future developments in the field.
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Affiliation(s)
- Xiaolian Xing
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Department of Neurology, Taiyuan Central Hospital, Taiyuan, Shanxi, China
| | - Hongwei Liu
- Department of Neurology, Taiyuan Central Hospital, Taiyuan, Shanxi, China
| | - Minheng Zhang
- Department of Gerontology, The First People's Hospital of Jinzhong, Yuci, Shanxi, China
| | - Yang Li
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Katola FO, Adana MY, Olajide OA. Inhibition of neuroinflammation and neuronal damage by the selective non-steroidal ERβ agonist AC-186. Inflamm Res 2024; 73:2109-2121. [PMID: 39361032 PMCID: PMC11632062 DOI: 10.1007/s00011-024-01952-y] [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: 06/21/2024] [Revised: 09/17/2024] [Accepted: 09/25/2024] [Indexed: 12/11/2024] Open
Abstract
BACKGROUND AC-186 (4-[4-4-Difluoro-1-(2-fluorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective oestrogen receptor modulator. This study investigated whether inhibition of neuroinflammation contributed to neuroprotective activity of this compound. METHODS BV-2 microglia were treated with AC-186 (0.65-5 μM) prior to stimulation with LPS (100 ng/mL). Levels of pro-inflammatory mediators and proteins were then evaluated. RESULTS Treatment of LPS-activated BV-2 microglia with AC-186 resulted in significant (p < 0.05) reduction in TNFα, IL-6, NO, PGE2, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186 induced significant (p < 0.05) increase in protein expression of ERβ, while enhancing ERE luciferase activity in BV-2 cells. Effects of the compound on oestrogen signalling in the microglia was confirmed in knockdown experiments which revealed a loss of anti-inflammatory activity following transfection with ERβ siRNA. In vitro neuroprotective activity of AC-186 was demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons. CONCLUSIONS This study established that AC-186 produces NF-κB-mediated anti-inflammatory activity, which is proposed as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-inflammatory activity of this compound is linked to its agonist effect on ERβ.
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Affiliation(s)
- Folashade O Katola
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK
- Current Address: Peter O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Misturah Y Adana
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK
- Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Olumayokun A Olajide
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK.
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Armstrong C, Luo D, Gretzinger A, Pandey D, Lipchik A, Todi SV, Dutta AK. Novel Piperazine Based Compounds Target Alzheimer's Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein. ACS Chem Neurosci 2024; 15:3901-3914. [PMID: 39501783 DOI: 10.1021/acschemneuro.4c00220] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2025] Open
Abstract
Alzheimer's disease (AD) is the leading form of dementia in the United States and the world. The pathophysiology of AD is complex and multifaceted. Accumulation of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of AD. The aggregation of amyloid β (senile plaques) and tau tangles (NFTs) results in the death of neurons in the cortex and hippocampus, which manifests itself in cognitive decline and memory loss. Current therapies rely on conventional approaches that have only treated the underlying symptoms without disease modification. Data from clinical studies point to a complex role of amyloid β (Aβ) in a way that enhances the tau phenotype throughout the disease process. To address the co-pathogenic role of Aβ and tau, we undertook development of multitarget compounds aiming at both tau and Aβ to slow or stop disease progression and provide neuroprotection. Here, we demonstrate a dose-dependent effect of the novel test compounds that inhibit aggregation of AcPHF6 (a shorter version of tau protein) and Aβ1-42 peptides in thioflavin T fluorescent assays. The compounds were also shown to disaggregate preformed aggregates dose dependently. To further validate these findings, circular dichroism experiments were carried out to examine the nature of inhibition. Additionally, transmission electron microscopy experiments were carried out to gain insights into the morphologies of aggregates obtained from dose-dependent inhibition of AcPHF6 and Aβ1-42 as well as dissociation of preformed aggregates from these peptides. Compounds D-687 and D-688 reversed Aβ1-42 induced toxicity in SH-SH5Y cells, significantly demonstrating neuroprotective properties. Finally, in a study with Drosophila melanogaster expressing human tau protein isoform (2N4R) in all the neurons, compound D-688 significantly increased the survival of flies compared to vehicle treated controls. Future studies will further examine the neuroprotective properties of these lead compounds in various animal models.
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Affiliation(s)
- Christopher Armstrong
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, United States
| | - Dan Luo
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, United States
| | - Anna Gretzinger
- Department of Pharmacology, Wayne State University, Detroit, Michigan 48201, United States
| | - Deepti Pandey
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, United States
| | - Andrew Lipchik
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, United States
| | - Sokol V Todi
- Department of Pharmacology, Wayne State University, Detroit, Michigan 48201, United States
- Department of Neurology, Wayne State University, Detroit, Michigan 48201, United States
| | - Aloke K Dutta
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, United States
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Wang H, Zhao T, Zeng J, Zhang R, Pu L, Qian S, Xu S, Jiang Y, Pan L, Dai X, Guo X, Han L. Methods and clinical biomarker discovery for targeted proteomics using Olink technology. Proteomics Clin Appl 2024; 18:e2300233. [PMID: 38726756 DOI: 10.1002/prca.202300233] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 03/12/2024] [Accepted: 04/09/2024] [Indexed: 11/18/2024]
Abstract
PURPOSE This paper is to offer insights for designing research utilizing Olink technology to identify biomarkers and potential therapeutic targets for disease treatment. EXPERIMENTAL DESIGN We discusses the application of Olink technology in oncology, cardiovascular, respiratory and immune-related diseases, and Outlines the advantages and limitations of Olink technology. RESULTS Olink technology simplifies the search for therapeutic targets, advances proteomics research, reveals the pathogenesis of diseases, and ultimately helps patients develop precision treatments. CONCLUSIONS Although proteomics technology has been rapidly developed in recent years, each method has its own disadvantages, so in the future research, more methods should be selected for combined application to verify each other.
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Affiliation(s)
- Han Wang
- Department of Clinical Epidemiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Tian Zhao
- Department of Clinical Epidemiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Jingjing Zeng
- Department of Clinical Epidemiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Ruijie Zhang
- Department of Clinical Epidemiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Liyuan Pu
- Department of Clinical Epidemiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Suying Qian
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Shan Xu
- Shen zhen Nanshan Center for Chronic Disease Control, Shenzhen, Guangdong, China
| | - Yannan Jiang
- Department of Clinical Epidemiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Lifang Pan
- Department of Clinical Epidemiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Xiaoyu Dai
- Department of Anus & Intestine Surgery, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Xu Guo
- Department of Rehabilitation Medicine, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Liyuan Han
- Department of Clinical Epidemiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
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Gürbüzer N, Ozkaya AL. Inflammatory Burden Index (IBI) and Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score in Alzheimer's Disease: A Retrospective Comparative Study. Cureus 2024; 16:e69148. [PMID: 39398776 PMCID: PMC11467697 DOI: 10.7759/cureus.69148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 10/15/2024] Open
Abstract
OBJECTIVE This study aimed to evaluate the differences between Alzheimer's disease (AD) patients and controls in biochemistry and peripheral hemogram parameters neutrophil, lymphocyte, monocyte, platelet, and C-reactive protein (CRP) levels, lipid profile, inflammatory burden index (IBI), and hemoglobin, albumin, lymphocyte, and platelet (HALP) score and the relationship between inflammatory and immunonutritive biomarkers and cognitive impairment in patients. METHOD Data from 79 patients with AD and 42 controls were included in the study. Medical data of the participants were obtained from hospital records. IBI was obtained by using the following formula: CRP × neutrophil/lymphocyte. HALP score was calculated as (hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L))/platelets (/L). RESULTS Neutrophil count (p=0.003, effect size=0.60), CRP level (p<0.001, effect size=0.87), and IBI (p<0.001, effect size=0.93) were significantly higher in AD patients compared to the control group; hemoglobin (p<0.001, effect size=1.03), lymphocyte count (p<0.001, effect size=0.78), albumin level (p<0.001, effect size=1.31), and HALP score (p<0.001, effect size=0.85) were lower. According to the Standardized Mini Mental Test (SMMT) score, neutrophil count (p=0.001), CRP (p<0.001), and IBI (p<0.001) were significantly higher and lymphocyte count (p=0.001) and HALP score (p<0.001) were lower in the group with severe cognitive impairment. Albumin levels were highest in the group with mild cognitive impairment. In the patient group, there was a moderately significant negative relationship between SMMT score and age (p<0.001, r=-0.437), neutrophil count (p=0.033, r=-0.240), CRP (p<0.001, r=-0.451), and IBI (p<0.001, r=-0.538). Lymphocyte count (p<0.001, r=0.412), high-density lipoprotein (HDL) (p=0.049, r=0.223), albumin levels (p=0.001, r=0.357), and HALP score (p<0.001, r=0.486) were moderately positively associated with SMMT score. Age (β=-0.437, p<0.001), HALP score (β=0.403, p<0.001), and IBI (β=-0.322, p=0.004) were found to be predictors for the severity of cognitive impairment. CONCLUSION Our results revealed that inflammation and immunonutritive status play an important role in the pathogenesis of AD. Novel inflammatory and immunonutritive biomarkers, and IBI and HALP score may be promising clinical tools that may pave the way for more personalized treatment strategies and interventions for patients.
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11
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Chakrabarti KS, Bakhtiari D, Rezaei-Ghaleh N. Bifurcations in coupled amyloid-β aggregation-inflammation systems. NPJ Syst Biol Appl 2024; 10:80. [PMID: 39080352 PMCID: PMC11289389 DOI: 10.1038/s41540-024-00408-7] [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: 03/27/2024] [Accepted: 07/23/2024] [Indexed: 08/02/2024] Open
Abstract
A complex interplay between various processes underlies the neuropathology of Alzheimer's disease (AD) and its progressive course. Several lines of evidence point to the coupling between Aβ aggregation and neuroinflammation and its role in maintaining brain homeostasis during the long prodromal phase of AD. Little is however known about how this protective mechanism fails and as a result, an irreversible and progressive transition to clinical AD occurs. Here, we introduce a minimal model of a coupled system of Aβ aggregation and inflammation, numerically simulate its dynamical behavior, and analyze its bifurcation properties. The introduced model represents the following events: generation of Aβ monomers, aggregation of Aβ monomers into oligomers and fibrils, induction of inflammation by Aβ aggregates, and clearance of various Aβ species. Crucially, the rates of Aβ generation and clearance are modulated by inflammation level following a Hill-type response function. Despite its relative simplicity, the model exhibits enormously rich dynamics ranging from overdamped kinetics to sustained oscillations. We then specify the region of inflammation- and coupling-related parameters space where a transition to oscillatory dynamics occurs and demonstrate how changes in Aβ aggregation parameters could shift this oscillatory region in parameter space. Our results reveal the propensity of coupled Aβ aggregation-inflammation systems to oscillatory dynamics and propose prolonged sustained oscillations and their consequent immune system exhaustion as a potential mechanism underlying the transition to a more progressive phase of amyloid pathology in AD. The implications of our results in regard to early diagnosis of AD and anti-AD drug development are discussed.
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Affiliation(s)
- Kalyan S Chakrabarti
- Department of Biological Science and Chemistry, Krea University, Sri City, India
| | | | - Nasrollah Rezaei-Ghaleh
- Heinrich Heine University (HHU) Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Physical Biology, Düsseldorf, Germany.
- Institute of Biological Information Processing, IBI-7: Structural Biochemistry, Forschungszentrum Jülich, Wilhelm-Johnen-Straße, Jülich, Germany.
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12
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Liu WY, Yu Y, Zang J, Liu Y, Li FR, Zhang L, Guo RB, Kong L, Ma LY, Li XT. Menthol-Modified Quercetin Liposomes with Brain-Targeting Function for the Treatment of Senescent Alzheimer's Disease. ACS Chem Neurosci 2024; 15:2283-2295. [PMID: 38780450 DOI: 10.1021/acschemneuro.4c00109] [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: 05/25/2024] Open
Abstract
Oxidative stress and neuroinflammation in the aging brain are correlated with the development of neurodegenerative diseases, such as Alzheimer's disease (AD). The blood-brain barrier (BBB) poses a significant challenge to the effective delivery of therapeutics for AD. Prior research has demonstrated that menthol (Men) can augment the permeability of the BBB. Consequently, in the current study, we modified Men on the surface of liposomes to construct menthol-modified quercetin liposomes (Men-Qu-Lips), designed to cross the BBB and enhance quercetin (Qu) concentration in the brain for improved therapeutic efficacy. The experimental findings indicate that Men-Qu-Lips exhibited good encapsulation efficiency and stability, successfully crossed the BBB, improved oxidative stress and neuroinflammation in the brains of aged mice, protected neurons, and enhanced their learning and memory abilities.
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Affiliation(s)
- Wan-Ying Liu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Yang Yu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Juan Zang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Yang Liu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Feng-Rui Li
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Lu Zhang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Rui-Bo Guo
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Liang Kong
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Ling-Yue Ma
- Department of Pharmacy, Peking University First Hospital, Beijing 100034, China
| | - Xue-Tao Li
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
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13
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Li X, Ramos-Rolón AP, Kass G, Pereira-Rufino LS, Shifman N, Shi Z, Volkow ND, Wiers CE. Imaging neuroinflammation in individuals with substance use disorders. J Clin Invest 2024; 134:e172884. [PMID: 38828729 PMCID: PMC11142750 DOI: 10.1172/jci172884] [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] [Indexed: 06/05/2024] Open
Abstract
Increasing evidence suggests a role of neuroinflammation in substance use disorders (SUDs). This Review presents findings from neuroimaging studies assessing brain markers of inflammation in vivo in individuals with SUDs. Most studies investigated the translocator protein 18 kDa (TSPO) using PET; neuroimmune markers myo-inositol, choline-containing compounds, and N-acetyl aspartate using magnetic resonance spectroscopy; and fractional anisotropy using MRI. Study findings have contributed to a greater understanding of neuroimmune function in the pathophysiology of SUDs, including its temporal dynamics (i.e., acute versus chronic substance use) and new targets for SUD treatment.
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Affiliation(s)
- Xinyi Li
- Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, Pennsylvania, USA
| | - Astrid P. Ramos-Rolón
- Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, Pennsylvania, USA
| | - Gabriel Kass
- Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, Pennsylvania, USA
| | - Lais S. Pereira-Rufino
- Departamento de Morfologia e Genética, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Naomi Shifman
- Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, Pennsylvania, USA
| | - Zhenhao Shi
- Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, Pennsylvania, USA
| | - Nora D. Volkow
- Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA
| | - Corinde E. Wiers
- Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, Pennsylvania, USA
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14
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Shang NY, Huang LJ, Lan JQ, Kang YY, Tang JS, Wang HY, Li XN, Sun Z, Chen QY, Liu MY, Wen ZP, Feng XH, Wu L, Peng Y. PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway. Acta Pharmacol Sin 2024; 45:1142-1159. [PMID: 38409216 PMCID: PMC11130211 DOI: 10.1038/s41401-024-01240-9] [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: 10/13/2023] [Accepted: 02/06/2024] [Indexed: 02/28/2024]
Abstract
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 μM) significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3β/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.
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Affiliation(s)
- Nian-Ying Shang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Long-Jian Huang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Jia-Qi Lan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Yu-Ying Kang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Jing-Shu Tang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Hong-Yue Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Xin-Nan Li
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Zhuo Sun
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Qiu-Yu Chen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Meng-Yao Liu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Zi-Peng Wen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Xin-Hong Feng
- Department of Neurology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Lei Wu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Ying Peng
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
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15
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Paprzycka O, Wieczorek J, Nowak I, Madej M, Strzalka-Mrozik B. Potential Application of MicroRNAs and Some Other Molecular Biomarkers in Alzheimer's Disease. Curr Issues Mol Biol 2024; 46:5066-5084. [PMID: 38920976 PMCID: PMC11202417 DOI: 10.3390/cimb46060304] [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: 03/30/2024] [Revised: 05/05/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024] Open
Abstract
Alzheimer's disease (AD) is the world's most common neurodegenerative disease, expected to affect up to one-third of the elderly population in the near future. Among the major challenges in combating AD are the inability to reverse the damage caused by the disease, expensive diagnostic tools, and the lack of specific markers for the early detection of AD. This paper highlights promising research directions for molecular markers in AD diagnosis, including the diagnostic potential of microRNAs. The latest molecular methods for diagnosing AD are discussed, with particular emphasis on diagnostic techniques prior to the appearance of full AD symptoms and markers detectable in human body fluids. A collection of recent studies demonstrates the promising potential of molecular methods in AD diagnosis, using miRNAs as biomarkers. Up- or downregulation in neurodegenerative diseases may not only provide a new diagnostic tool but also serve as a marker for differentiating neurodegenerative diseases. However, further research in this direction is needed.
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Affiliation(s)
- Olga Paprzycka
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (O.P.); (J.W.); (M.M.)
| | - Jan Wieczorek
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (O.P.); (J.W.); (M.M.)
| | - Ilona Nowak
- Silesia LabMed, Centre for Research and Implementation, Medical University of Silesia, 40-752 Katowice, Poland;
| | - Marcel Madej
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (O.P.); (J.W.); (M.M.)
- Silesia LabMed, Centre for Research and Implementation, Medical University of Silesia, 40-752 Katowice, Poland;
| | - Barbara Strzalka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (O.P.); (J.W.); (M.M.)
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16
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Dounavi ME, McKiernan E, Langsen M, Gregory S, Muniz-Terrera G, Prats-Sedano MA, Mada MO, Williams GB, Lawlor B, Naci L, Mackay C, Koychev I, Malhotra P, Ritchie K, Ritchie CW, Su L, Waldman AD, O’ Brien JT. Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors. Brain Commun 2024; 6:fcae138. [PMID: 38779354 PMCID: PMC11109818 DOI: 10.1093/braincomms/fcae138] [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: 07/24/2023] [Revised: 01/18/2024] [Accepted: 04/15/2024] [Indexed: 05/25/2024] Open
Abstract
Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.
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Affiliation(s)
- Maria-Eleni Dounavi
- Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK
| | - Elizabeth McKiernan
- Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK
| | - Michael Langsen
- Center for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Sarah Gregory
- Centre for Dementia Prevention, University of Edinburgh, Edinburgh, EH16 4UX, UK
| | - Graciela Muniz-Terrera
- Centre for Dementia Prevention, University of Edinburgh, Edinburgh, EH16 4UX, UK
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | | | - Marius Ovidiu Mada
- Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, CB2 7EF, UK
| | - Guy B Williams
- Department of Clinical Neurosciences and Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Brian Lawlor
- Institute of Neuroscience, Trinity College Dublin, University of Dublin, Dublin, D02 PX31, Ireland
| | - Lorina Naci
- Institute of Neuroscience, Trinity College Dublin, University of Dublin, Dublin, D02 PX31, Ireland
| | - Clare Mackay
- Department of Psychiatry, Oxford University, Oxford, OX3 7JX, UK
| | - Ivan Koychev
- Department of Psychiatry, Oxford University, Oxford, OX3 7JX, UK
| | - Paresh Malhotra
- Department of Brain Sciences, Imperial College Healthcare NHS Trust, London, W12 0NN, UK
| | - Karen Ritchie
- INM, Univ Montpellier, INSERM, Montpellier, 34090, France
| | - Craig W Ritchie
- Centre for Dementia Prevention, University of Edinburgh, Edinburgh, EH16 4UX, UK
| | - Li Su
- Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK
- Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK
| | - Adam D Waldman
- Center for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK
- Department of Brain Sciences, Imperial College Healthcare NHS Trust, London, W12 0NN, UK
| | - John T O’ Brien
- Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK
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17
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Pan Y, Chen J, Zhang Y, Ren Y, Wu Z, Xue Q, Zeng S, Fang C, Zhang H, Zhang L, Liu C, Zeng J. Second Near-Infrared Macrophage-Biomimetic Nanoprobes for Photoacoustic Imaging of Neuroinflammation. Mol Pharm 2024; 21:1804-1816. [PMID: 38466359 DOI: 10.1021/acs.molpharmaceut.3c01115] [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: 03/13/2024]
Abstract
Neuroinflammation is a significant pathological event involving the neurodegenerative process associated with many neurological disorders. Diagnosis and treatment of neuroinflammation in its early stage are essential for the prevention and management of neurological diseases. Herein, we designed macrophage membrane-coated photoacoustic (PA) probes (MSINPs), with targeting specificities based on naturally existing target-ligand interactions for the early diagnosis of neuroinflammation. The second near-infrared dye, IR1061, was doped into silica as the core and was encapsulated with a macrophage membrane. In vitro as well as in vivo, the MSINPs could target inflammatory cells via the inflammation chemotactic effect. PA imaging was used to trace the MSINPs in a neuroinflammation mouse model and showed a great targeted effect of MSINPs in the prefrontal cortex. Therefore, the biomimetic nanoprobe prepared in this study offers a new strategy for PA molecular imaging of neuroinflammation, which can enhance our understanding of the evolution of neuroinflammation in specific brain regions.
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Affiliation(s)
- Yingying Pan
- Department of Medical Ultrasound, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Jingqin Chen
- Research Center for Biomedical Optics and Molecular Imaging, Key Laboratory of Biomedical Imaging Science and System, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Yuling Zhang
- Shenzhen Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518116, China
| | - Yaguang Ren
- Research Center for Biomedical Optics and Molecular Imaging, Key Laboratory of Biomedical Imaging Science and System, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Zhifeng Wu
- Research Center for Biomedical Optics and Molecular Imaging, Key Laboratory of Biomedical Imaging Science and System, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Qiang Xue
- Research Center for Biomedical Optics and Molecular Imaging, Key Laboratory of Biomedical Imaging Science and System, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- Department of Ultrasound, Shenzhen People's Hospital, The Second Clinical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
| | - Silue Zeng
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Chihua Fang
- Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Hai Zhang
- Department of Ultrasound, Shenzhen People's Hospital, The Second Clinical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China
| | - Lingyan Zhang
- Lab of Molecular Imaging and Medical Intelligence, Department of Radiology, Longgang Central Hospital of Shenzhen, Shenzhen 518116, China
| | - Chengbo Liu
- Research Center for Biomedical Optics and Molecular Imaging, Key Laboratory of Biomedical Imaging Science and System, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Jie Zeng
- Department of Medical Ultrasound, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
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18
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Chen Z, Liu S, Zhou H, Wang M, Pei S, Wang R, Liu Z. UPLC-Q-TOF/MS based serum and urine metabolomics strategy to analyze the mechanism of nervonic acid in treating Alzheimer's disease. J Pharm Biomed Anal 2024; 240:115930. [PMID: 38157740 DOI: 10.1016/j.jpba.2023.115930] [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: 11/05/2023] [Revised: 12/07/2023] [Accepted: 12/17/2023] [Indexed: 01/03/2024]
Abstract
Nervonic acid is a natural component of breast milk and is frequently used as a food additive due to its excellent neuroprotective effects. Although it has been reported that nervonic acid may play a role in the recovery of human cognitive impairment, its specific mechanism of action is still unclear. In this study, the results of serum biochemical indexes showed that nervonic acid improved inflammation and reduced amyloid β peptide (Aβ) deposition and tau protein phosphorylation in Alzheimer's disease (AD) rats. Subsequently, we further used a metabolomics approach to investigate the potential mechanism of action of nervonic acid in the treatment of AD. The results of serum and urine metabolomics study showed that the intervention of nervonic acid significantly reversed the metabolic profile disorder in AD rats. A total of 52 metabolites were identified. They mainly involved linoleic acid metabolism, alpha-linolenic acid metabolism, phenylalanine metabolism and arachidonic acid metabolism, and all these metabolic pathways were associated with the emergence of inflammation in vivo. It suggests that the therapeutic effect of nervonic acid on AD is likely to be produced by ameliorating inflammation. The results obtained in this study provide new insights into the mechanism of nervonic acid treatment of AD and lay a foundation for the clinical application of nervonic acid in the treatment of Alzheimer's disease.
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Affiliation(s)
- Ziyi Chen
- School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
| | - Shu Liu
- National Center of Mass Spectrometry in Changchun & Jilin Provincial Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
| | - Hui Zhou
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Institute of Plant Resources, Dalian Minzu University, Dalian 116029, China
| | - Meiyuan Wang
- School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
| | - Shuhua Pei
- School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
| | - Rongjin Wang
- School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
| | - Zhongying Liu
- School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
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Bai H, Zeng HM, Zhang QF, Hu YZ, Deng FF. Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer's disease. World J Clin Cases 2024; 12:1063-1075. [PMID: 38464932 PMCID: PMC10921302 DOI: 10.12998/wjcc.v12.i6.1063] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/21/2023] [Accepted: 01/29/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a serious disease causing human dementia and social problems. The quality of life and prognosis of AD patients have attracted much attention. The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important. AIM To study the relationship among cognitive dysfunction, abnormal cellular immune function, neuroimaging results and poor prognostic factors in patients. METHODS A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020. Collect cognitive dysfunction performance characteristics, laboratory test data and neuroimaging data from medical records within 24 h of admission, including Mini Mental State Examination Scale score, drawing clock test, blood T lymphocyte subsets, and neutrophils and lymphocyte ratio (NLR), disturbance of consciousness, extrapyramidal symptoms, electroencephalogram (EEG) and head nucleus magnetic spectroscopy (MRS) and other data. Multivariate logistic regression analysis was used to determine independent prognostic factors. the modified Rankin scale (mRS) was used to determine whether the prognosis was good. The correlation between drug treatment and prognostic mRS score was tested by the rank sum test. RESULTS Univariate analysis showed that abnormal cellular immune function, extrapyramidal symptoms, obvious disturbance of consciousness, abnormal EEG, increased NLR, abnormal MRS, and complicated pneumonia were related to the poor prognosis of AD patients. Multivariate logistic regression analysis showed that the decrease in the proportion of T lymphocytes in the blood after abnormal cellular immune function (odd ratio: 2.078, 95% confidence interval: 1.156-3.986, P < 0.05) was an independent risk factor for predicting the poor prognosis of AD. The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score (r = 0.578, P < 0.05). CONCLUSION The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD. It is recommended that the proportion of T lymphocytes < 55% is used as the cut-off threshold for predicting the poor prognosis of AD. The early and continuous drug treatment is associated with a good prognosis.
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Affiliation(s)
- Hua Bai
- Department of Neurology, The Third Affiliated Hospital of Guizhou Medical University in China, Duyun 558099, Guizhou Province, China
| | - Hong-Mei Zeng
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
| | - Qi-Fang Zhang
- Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Yue-Zhi Hu
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
| | - Fei-Fei Deng
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
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20
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Sahara N, Higuchi M. Diagnostic and therapeutic targeting of pathological tau proteins in neurodegenerative disorders. FEBS Open Bio 2024; 14:165-180. [PMID: 37746832 PMCID: PMC10839408 DOI: 10.1002/2211-5463.13711] [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: 07/24/2023] [Revised: 09/06/2023] [Accepted: 09/22/2023] [Indexed: 09/26/2023] Open
Abstract
Tauopathies, characterized by fibrillar tau accumulation in neurons and glial cells, constitute a major neuropathological category of neurodegenerative diseases. Neurofibrillary tau lesions are strongly associated with cognitive deficits in these diseases, but the causal mechanisms underlying tau-induced neuronal dysfunction remain unresolved. Recent advances in cryo-electron microscopy examination have revealed various core structures of tau filaments from different tauopathy patients, which can be used to classify tauopathies. In vivo visualization of tau pathology is now available using several tau positron emission tomography tracers. Among these radioprobes, PM-PBB3 allows high-contrast imaging of tau deposits in the brains of patients with diverse disorders and tauopathy mouse models. Selective degradation of pathological tau species by the ubiquitin-proteasome system or autophagy machinery is a potential therapeutic strategy. Alternatively, the non-cell-autonomous clearance of pathological tau species through neuron-glia networks could be reinforced as a disease-modifying treatment. In addition, the development of neuroinflammatory biomarkers is required for understanding the contribution of immunocompetent cells in the brain to preventing neurodegeneration. This review provides an overview of the current research and development of diagnostic and therapeutic agents targeting divergent tau pathologies.
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Affiliation(s)
- Naruhiko Sahara
- Department of Functional Brain Imaging, Institute for Quantum Medical SciencesNational Institutes for Quantum Science and TechnologyChibaJapan
| | - Makoto Higuchi
- Department of Functional Brain Imaging, Institute for Quantum Medical SciencesNational Institutes for Quantum Science and TechnologyChibaJapan
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21
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Chu J, Zhang W, Liu Y, Gong B, Ji W, Yin T, Gao C, Liangwen D, Hao M, Chen C, Zhuang J, Gao J, Yin Y. Biomaterials-based anti-inflammatory treatment strategies for Alzheimer's disease. Neural Regen Res 2024; 19:100-115. [PMID: 37488851 PMCID: PMC10479833 DOI: 10.4103/1673-5374.374137] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/28/2023] [Accepted: 03/28/2023] [Indexed: 07/26/2023] Open
Abstract
The current therapeutic drugs for Alzheimer's disease only improve symptoms, they do not delay disease progression. Therefore, there is an urgent need for new effective drugs. The underlying pathogenic factors of Alzheimer's disease are not clear, but neuroinflammation can link various hypotheses of Alzheimer's disease; hence, targeting neuroinflammation may be a new hope for Alzheimer's disease treatment. Inhibiting inflammation can restore neuronal function, promote neuroregeneration, reduce the pathological burden of Alzheimer's disease, and improve or even reverse symptoms of Alzheimer's disease. This review focuses on the relationship between inflammation and various pathological hypotheses of Alzheimer's disease; reports the mechanisms and characteristics of small-molecule drugs (e.g., nonsteroidal anti-inflammatory drugs, neurosteroids, and plant extracts); macromolecule drugs (e.g., peptides, proteins, and gene therapeutics); and nanocarriers (e.g., lipid-based nanoparticles, polymeric nanoparticles, nanoemulsions, and inorganic nanoparticles) in the treatment of Alzheimer's disease. The review also makes recommendations for the prospective development of anti-inflammatory strategies based on nanocarriers for the treatment of Alzheimer's disease.
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Affiliation(s)
- Jianjian Chu
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
| | - Weicong Zhang
- School of Pharmacy, University College London, London, UK
| | - Yan Liu
- Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Clinical Pharmacy Innovation Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baofeng Gong
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
| | - Wenbo Ji
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
| | - Tong Yin
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
| | - Chao Gao
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
| | - Danqi Liangwen
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Mengqi Hao
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Cuimin Chen
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jianhua Zhuang
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
| | - Jie Gao
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - You Yin
- Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, China
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22
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He J, Liu F, Xu T, Ma J, Yu H, Zhao J, Xie Y, Luo L, Yang Q, Lou T, He L, Sun D. The role of hydrogen therapy in Alzheimer's disease management: Insights into mechanisms, administration routes, and future challenges. Biomed Pharmacother 2023; 168:115807. [PMID: 37913734 DOI: 10.1016/j.biopha.2023.115807] [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: 08/25/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/03/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly. While conventional pharmacological therapies remain the primary treatment for AD, their efficacy is limited effectiveness and often associated with significant side effects. This underscores the urgent need to explore alternative, non-pharmacological interventions. Oxidative stress has been identified as a central player in AD pathology, influencing various aspects including amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, mitochondrial dysfunction, and synaptic dysfunction. Among the emerging non-drug approaches, hydrogen therapy has garnered attention for its potential in mitigating these pathological conditions. This review provides a comprehensively overview of the therapeutic potential of hydrogen in AD. We delve into its mechanisms of action, administration routes, and discuss the current challenges and future prospects, with the aim of providing valuable insights to facilitate the clinical application of hydrogen-based therapies in AD management.
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Affiliation(s)
- Jiaxuan He
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Fan Liu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Ting Xu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Jiahui Ma
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Haiyang Yu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Jing Zhao
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Yanyan Xie
- The Affiliated Kangning Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Li Luo
- Dongguan Hospital, Southern Medical University, Dongguan 523059, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China
| | - Ting Lou
- Yiwu Center for Disease Control and Prevention, Yiwu 322000, China.
| | - Luqing He
- Department of Science and Education, the Third People's Hospital Health Care Group of Cixi, Ningbo 315300, China.
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China.
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23
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Zhang Q, Yan Y. The role of natural flavonoids on neuroinflammation as a therapeutic target for Alzheimer's disease: a narrative review. Neural Regen Res 2023; 18:2582-2591. [PMID: 37449593 DOI: 10.4103/1673-5374.373680] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023] Open
Abstract
Alzheimer's disease is a neurodegenerative disease that affects a large proportion of older adult people and is characterized by memory loss, progressive cognitive impairment, and various behavioral disturbances. Although the pathological mechanisms underlying Alzheimer's disease are complex and remain unclear, previous research has identified two widely accepted pathological characteristics: extracellular neuritic plaques containing amyloid beta peptide, and intracellular neurofibrillary tangles containing tau. Furthermore, research has revealed the significant role played by neuroinflammation over recent years. The inflammatory microenvironment mainly consists of microglia, astrocytes, the complement system, chemokines, cytokines, and reactive oxygen intermediates; collectively, these factors can promote the pathological process and aggravate the severity of Alzheimer's disease. Therefore, the development of new drugs that can target neuroinflammation will be a significant step forward for the treatment of Alzheimer's disease. Flavonoids are plant-derived secondary metabolites that possess various bioactivities. Previous research found that multiple natural flavonoids could exert satisfactory treatment effects on the neuroinflammation associated with Alzheimer's disease. In this review, we describe the pathogenesis and neuroinflammatory processes of Alzheimer's disease, and summarize the effects and mechanisms of 13 natural flavonoids (apigenin, luteolin, naringenin, quercetin, morin, kaempferol, fisetin, isoquercitrin, astragalin, rutin, icariin, mangiferin, and anthocyanin) derived from plants or medicinal herbs on neuroinflammation in Alzheimer's disease. As an important resource for the development of novel compounds for the treatment of critical diseases, it is essential that we focus on the exploitation of natural products. In particular, it is vital that we investigate the effects of flavonoids on the neuroinflammation associated with Alzheimer's disease in greater detail.
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Affiliation(s)
- Qian Zhang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education; College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi Province, China
| | - Yaping Yan
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education; College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi Province, China
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24
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Lee H, Kim Y, Aziz H, Kang DM, Lee J, Lee S, Jung S, Hyeon S, Choo H, Nam G, Kim YK, Lim S, Min SJ. Synthesis and biological evaluation of indane-based fluorescent probes for detection of amyloid-β aggregates in Alzheimer's disease. Bioorg Med Chem 2023; 95:117513. [PMID: 37931520 DOI: 10.1016/j.bmc.2023.117513] [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: 09/26/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/08/2023]
Abstract
In this article, the development of fluorescent imaging probes for the detection of Alzheimer's disease (AD)-associated protein aggregates is described. Indane derivatives with a donor-π-acceptor (D-π-A) structure were designed and synthesized. The probes were evaluated for their ability to bind to β-amyloid (Aβ) protein aggregates, which are a key pathological hallmark of AD. The results showed that several probes exhibited significant changes in fluorescence intensity at wavelengths greater than 600 nm when they were bound to Aβ aggregates compared to the Aβ monomeric form. Among the tested probes, four D-π-A type indane derivatives showed promising binding selectivity to Aβ aggregates over non-specific proteins such as bovine serum albumin (BSA). The molecular docking study showed that our compounds were appropriately located along the Aβ fibril axis through the hydrophobic tunnel structure. Further analysis revealed that the most active compound having dimethylaminopyridyl group as an election donor and dicyano group as an electron acceptor could effectively stain Aβ plaques in brain tissue samples from AD transgenic mice. These findings suggest that our indane-based compounds have the potential to serve as fluorescent probes for the detection and monitoring of Aβ aggregation in AD.
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Affiliation(s)
- Hyunseung Lee
- Department of Applied Chemistry, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Yihoon Kim
- Department of Applied Chemistry, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Hira Aziz
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea
| | - Dong-Min Kang
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Jaewoon Lee
- Department of Applied Chemistry, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea; Center for Bionano Intelligence Education and Research, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Sujin Lee
- Department of Applied Chemistry, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea; Center for Bionano Intelligence Education and Research, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Sunhwa Jung
- Department of Applied Chemistry, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea; Center for Bionano Intelligence Education and Research, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Suyeon Hyeon
- Department of Applied Chemistry, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Hyunah Choo
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea
| | - Ghilsoo Nam
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea
| | - Yun Kyung Kim
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea
| | - Sungsu Lim
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
| | - Sun-Joon Min
- Department of Applied Chemistry, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea; Center for Bionano Intelligence Education and Research, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea; Department of Chemical & Molecular Engineering, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea.
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25
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Eslami S, Hosseinzadeh Shakib N, Fooladfar Z, Nasrollahian S, Baghaei S, Mosaddad SA, Motamedifar M. The role of periodontitis-associated bacteria in Alzheimer's disease: A narrative review. J Basic Microbiol 2023; 63:1059-1072. [PMID: 37311215 DOI: 10.1002/jobm.202300250] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/01/2023] [Accepted: 06/03/2023] [Indexed: 06/15/2023]
Abstract
Alzheimer's disease causes memory loss and dementia in older adults through a neurodegenerative mechanism. Despite the pathophysiological clarification of this cognitive disorder, novel molecular and cellular pathways should be identified to determine its exact mechanism. Alzheimer's disease (AD) is pathologically characterized by senile plaques comprising beta-amyloid and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau as a microtubule-associated protein with a key role in the pathogenesis of AD. Periodontitis through inflammatory pathways is a risk factor for deteriorating cognitive impairment in AD patients. Poor oral hygiene coupled with immunocompromised status in older adults causes periodontal diseases and chronic inflammations through an oral bacterial imbalance. Toxic bacterial products, including bacteria themselves, can reach the central nervous system through the bloodstream and evoke inflammatory responses. The present review was conducted to investigate relationships between AD and periodontitis-involved bacteria as a risk factor.
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Affiliation(s)
- Saba Eslami
- Research Central Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Zahra Fooladfar
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sina Nasrollahian
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Baghaei
- Student Research Committee, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Ali Mosaddad
- Student Research Committee, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Motamedifar
- HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
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26
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Aili M, Zhou K, Zhan J, Zheng H, Luo F. Anti-inflammatory role of gold nanoparticles in the prevention and treatment of Alzheimer's disease. J Mater Chem B 2023; 11:8605-8621. [PMID: 37615596 DOI: 10.1039/d3tb01023f] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that causes memory and cognitive dysfunction and reduces a person's decision-making and reasoning functions. AD is the leading cause of dementia in the elderly. Patients with AD have increased expression of pro-inflammatory cytokines in the nervous system, and the sustained inflammatory response impairs neuronal function. Meanwhile, long-term use of anti-inflammatory drugs can reduce the incidence of AD to some extent. This confirms that anti-neuroinflammation may be an effective treatment for AD. Gold nanoparticles (AuNPs) are an emerging nanomaterial with promising physicochemical properties, anti-inflammatory and antioxidant. AuNPs reduce neuroinflammation by inducing macrophage polarization toward the M2 phenotype, reducing pro-inflammatory cytokine expression, blocking leukocyte adhesion, and decreasing oxidative stress. Therefore, AuNPs are gradually attracting the interest of scholars and are used for treating inflammatory diseases and drug delivery. Herein, we explored the role and mechanism of AuNPs in treating neuroinflammation in AD. The use of AuNPs for treating AD is a topic worth exploring in the future, not only to help solve a global public health problem but also to provide a reference for treating other neuroinflammatory diseases.
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Affiliation(s)
- Munire Aili
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China.
| | - Kebing Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China.
| | - Jun Zhan
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Huaping Zheng
- Department of Dermatology, Rare Diseases Center, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Feng Luo
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China.
- Department of Prosthodontics, West China School of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nanlu, Chengdu 610041, China
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27
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Li Y, Xu H, Wang H, Yang K, Luan J, Wang S. TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease. Biomed Pharmacother 2023; 165:115218. [PMID: 37517293 DOI: 10.1016/j.biopha.2023.115218] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/01/2023] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to mechanistically inhibit the progression of Alzheimer's disease, and most drugs only provide symptom relief and do not fundamentally reverse AD. Current studies show that triggering receptor expressed on myeloid cells 2 (TREM2) is predominantly expressed in microglia of the central nervous system (CNS) and is involved in microglia proliferation, survival, migration and phagocytosis. The current academic view suggests that TREM2 and its ligands have CNS protective effects in AD. Specifically, TREM2 acts by regulating the function of microglia and promoting the clearance of neuronal toxic substances and abnormal proteins by microglia. In addition, TREM2 is also involved in regulating inflammatory response and cell signaling pathways, affecting the immune response and regulatory role of microglia. Although the relationship between TREM2 and Alzheimer's disease has been extensively studied, its specific mechanism of action is not fully understood. The purpose of this review is to provide a comprehensive analysis of the research of TREM2, including its regulation of the inflammatory response, lipid metabolism and phagocytosis in microglia of CNS in AD, and to explore the potential application prospects as well as limitations of targeting TREM2 for the treatment of AD.
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Affiliation(s)
- Yueran Li
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China
| | - Huifang Xu
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China
| | - Huifang Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China
| | - Kui Yang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China
| | - Sheng Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China.
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28
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Neumann KD, Broshek DK, Newman BT, Druzgal TJ, Kundu BK, Resch JE. Concussion: Beyond the Cascade. Cells 2023; 12:2128. [PMID: 37681861 PMCID: PMC10487087 DOI: 10.3390/cells12172128] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/14/2023] [Accepted: 08/17/2023] [Indexed: 09/09/2023] Open
Abstract
Sport concussion affects millions of athletes each year at all levels of sport. Increasing evidence demonstrates clinical and physiological recovery are becoming more divergent definitions, as evidenced by several studies examining blood-based biomarkers of inflammation and imaging studies of the central nervous system (CNS). Recent studies have shown elevated microglial activation in the CNS in active and retired American football players, as well as in active collegiate athletes who were diagnosed with a concussion and returned to sport. These data are supportive of discordance in clinical symptomology and the inflammatory response in the CNS upon symptom resolution. In this review, we will summarize recent advances in the understanding of the inflammatory response associated with sport concussion and broader mild traumatic brain injury, as well as provide an outlook for important research questions to better align clinical and physiological recovery.
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Affiliation(s)
- Kiel D. Neumann
- Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;
| | - Donna K. Broshek
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22903, USA;
| | - Benjamin T. Newman
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903, USA; (B.T.N.); (T.J.D.); (B.K.K.)
| | - T. Jason Druzgal
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903, USA; (B.T.N.); (T.J.D.); (B.K.K.)
| | - Bijoy K. Kundu
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903, USA; (B.T.N.); (T.J.D.); (B.K.K.)
| | - Jacob E. Resch
- Department of Kinesiology, University of Virginia, Charlottesville, VA 22903, USA
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29
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Pacheco-Sánchez B, Tovar R, Ben Rabaa M, Sánchez-Salido L, Vargas A, Suárez J, Rodríguez de Fonseca F, Rivera P. Sex-Dependent Altered Expression of Cannabinoid Signaling in Hippocampal Astrocytes of the Triple Transgenic Mouse Model of Alzheimer's Disease: Implications for Controlling Astroglial Activity. Int J Mol Sci 2023; 24:12598. [PMID: 37628778 PMCID: PMC10454447 DOI: 10.3390/ijms241612598] [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: 05/31/2023] [Revised: 07/28/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
Alzheimer's disease (AD) is a common neurodegenerative disease. In AD-associated neuroinflammation, astrocytes play a key role, finding glial activation both in patients and in animal models. The endocannabinoid system (ECS) is a neurolipid signaling system with anti-inflammatory and neuroprotective properties implicated in AD. Astrocytes respond to external cannabinoid signals and also have their own cannabinoid signaling. Our main objective is to describe the cannabinoid signaling machinery present in hippocampal astrocytes from 3×Tg-AD mice to determine if they are actively involved in the neurodegenerative process. Primary cultures of astrocytes from the hippocampus of 3×Tg-AD and non-Tg offspring were carried out. We analyzed the gene expression of astrogliosis markers, the main components of the ECS and Ca2+ signaling. 3×Tg-AD hippocampal astrocytes show low inflammatory activity (Il1b, Il6, and Gls) and Ca2+ flow (P2rx5 and Mcu), associated with low cannabinoid signaling (Cnr1 and Cnr2). These results were more evident in females. Our study corroborates glial involvement in AD pathology, in which cannabinoid signaling plays an important role. 3×Tg-AD mice born with hippocampal astrocytes with differential gene expression of the ECS associated with an innate attenuation of their activity. In addition, we show that there are sex differences from birth in this AD animal, which should be considered when investigating the pathogenesis of the disease.
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Affiliation(s)
- Beatriz Pacheco-Sánchez
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain; (B.P.-S.); (R.T.); (M.B.R.); (L.S.-S.); (A.V.); (J.S.)
| | - Rubén Tovar
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain; (B.P.-S.); (R.T.); (M.B.R.); (L.S.-S.); (A.V.); (J.S.)
| | - Meriem Ben Rabaa
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain; (B.P.-S.); (R.T.); (M.B.R.); (L.S.-S.); (A.V.); (J.S.)
- Molecular Biotechnology, FH Campus Wien, University for Applied Sciences, Favoritenstraße 222, 1100 Vienna, Austria
| | - Lourdes Sánchez-Salido
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain; (B.P.-S.); (R.T.); (M.B.R.); (L.S.-S.); (A.V.); (J.S.)
| | - Antonio Vargas
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain; (B.P.-S.); (R.T.); (M.B.R.); (L.S.-S.); (A.V.); (J.S.)
| | - Juan Suárez
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain; (B.P.-S.); (R.T.); (M.B.R.); (L.S.-S.); (A.V.); (J.S.)
- Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Universidad de Málaga, 29010 Málaga, Spain
| | - Fernando Rodríguez de Fonseca
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain; (B.P.-S.); (R.T.); (M.B.R.); (L.S.-S.); (A.V.); (J.S.)
| | - Patricia Rivera
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain; (B.P.-S.); (R.T.); (M.B.R.); (L.S.-S.); (A.V.); (J.S.)
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Li Y, Zhang ZH, Huang SL, Yue ZB, Yin XS, Feng ZQ, Zhang XG, Song GL. Whey protein powder with milk fat globule membrane attenuates Alzheimer's disease pathology in 3×Tg-AD mice by modulating neuroinflammation through the peroxisome proliferator-activated receptor γ signaling pathway. J Dairy Sci 2023; 106:5253-5265. [PMID: 37414601 DOI: 10.3168/jds.2023-23254] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 02/20/2023] [Indexed: 07/08/2023]
Abstract
Whey protein powder (PP), which is mainly derived from bovine milk, is rich in milk fat globule membrane (MFGM). The MGFM has been shown to play a role in promoting neuronal development and cognition in the infant brain. However, its role in Alzheimer's disease (AD) has not been elucidated. Here, we showed that the cognitive ability of 3×Tg-AD mice (a triple-transgenic mouse model of AD) could be improved by feeding PP to mice for 3 mo. In addition, PP ameliorated amyloid peptide deposition and tau hyperphosphorylation in the brains of AD mice. We found that PP could alleviate AD pathology by inhibiting neuroinflammation through the peroxisome proliferator-activated receptor γ (PPARγ)-nuclear factor-κB signaling pathway in the brains of AD mice. Our study revealed an unexpected role of PP in regulating the neuroinflammatory pathology of AD in a mouse model.
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Affiliation(s)
- Yu Li
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China, 518060; Shenzhen Bay Laboratory, Shenzhen, China, 518000
| | - Zhong-Hao Zhang
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China, 518060; Shenzhen Bay Laboratory, Shenzhen, China, 518000
| | - Shao-Ling Huang
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China, 518060
| | - Zhong-Bao Yue
- ByHealth Institute of Nutrition and Health, Guangzhou, China, 510000
| | - Xue-Song Yin
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China, 518060
| | - Zi-Qi Feng
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China, 518060
| | - Xu-Guang Zhang
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China, 518060; ByHealth Institute of Nutrition and Health, Guangzhou, China, 510000.
| | - Guo-Li Song
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China, 518060; Shenzhen Bay Laboratory, Shenzhen, China, 518000; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China, 518000.
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31
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McKiernan E, Su L, O'Brien J. MRS in neurodegenerative dementias, prodromal syndromes and at-risk states: A systematic review of the literature. NMR IN BIOMEDICINE 2023; 36:e4896. [PMID: 36624067 DOI: 10.1002/nbm.4896] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 12/21/2022] [Accepted: 01/04/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND In recent years, MRS has benefited from increased MRI field strengths, new acquisition protocols and new processing techniques. This review aims to determine how this has altered our understanding of MRS neurometabolic markers in neurodegenerative dementias. METHODS Our systematic review of human in vivo MRS literature since 2002 pertains to Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease dementia, frontotemporal dementia (FTD), prodromal and 'at-risk' states. Studies using field strengths of 3 T or more were included. RESULTS Of 85 studies, AD and/or mild cognitive impairment (MCI) were the most common conditions of interest (58 papers, 68%). Only 14 (16%) studies included other dementia syndromes and 13 (15%) investigated 'at-risk' cohorts. Earlier findings of lower N-acetylaspartate and higher myo-inositol were confirmed. Additionally, lower choline and creatine in AD and MCI were reported, though inconsistently. Previously challenging-to-measure metabolites (glutathione, glutamate and gamma-aminobutyric acid) were reportedly lower in AD, FTD and DLB compared with controls. DISCUSSION Increasing field strength alongside targeted acquisition protocols has revealed additional metabolite changes. Most studies were small and regional metabolite differences between dementia types may not have been captured due to the predominant placement of voxels in the posterior cingulate cortex. The standard of data collection, quality control and analysis is improving due to greater consensus regarding acquisition and processing techniques. Ongoing harmonization of techniques, creation of larger and longitudinal cohorts, and placement of MRS voxels in more diverse regions will strengthen future research.
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Affiliation(s)
- Elizabeth McKiernan
- Department of Psychiatry, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Li Su
- Department of Psychiatry, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
- Neuroscience Institute, University of Sheffield, Sheffield, UK
| | - John O'Brien
- Department of Psychiatry, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
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Jett S, Boneu C, Zarate C, Carlton C, Kodancha V, Nerattini M, Battista M, Pahlajani S, Williams S, Dyke JP, Mosconi L. Systematic review of 31P-magnetic resonance spectroscopy studies of brain high energy phosphates and membrane phospholipids in aging and Alzheimer's disease. Front Aging Neurosci 2023; 15:1183228. [PMID: 37273652 PMCID: PMC10232902 DOI: 10.3389/fnagi.2023.1183228] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 05/02/2023] [Indexed: 06/06/2023] Open
Abstract
Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aβ) plaques. In vivo probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used 18F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in vivo in the human brain. 31Phosphorus-magnetic resonance spectroscopy (31P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the 31P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of 31P-MRS measures as biomarkers for the early detection of AD.
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Affiliation(s)
- Steven Jett
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
| | - Camila Boneu
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
| | - Camila Zarate
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
| | - Caroline Carlton
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
| | - Vibha Kodancha
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
| | - Matilde Nerattini
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
- Nuclear Medicine Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Michael Battista
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
| | - Silky Pahlajani
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
- Department of Radiology, Weill Cornell Medical College, New York, NY, United States
| | - Schantel Williams
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
| | - Jonathan P. Dyke
- Department of Radiology, Weill Cornell Medical College, New York, NY, United States
| | - Lisa Mosconi
- Department of Neurology, Weill Cornell Medical College, New York, NY, United States
- Department of Radiology, Weill Cornell Medical College, New York, NY, United States
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Mao R, Xu S, Sun G, Yu Y, Zuo Z, Wang Y, Yang K, Zhang Z, Yang W. Triptolide injection reduces Alzheimer's disease-like pathology in mice. Synapse 2023; 77:e22261. [PMID: 36633502 DOI: 10.1002/syn.22261] [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: 03/24/2022] [Revised: 12/21/2022] [Accepted: 01/08/2023] [Indexed: 01/13/2023]
Abstract
Triptolide is an epoxidized diterpene lactone isolated from Tripterygium wilfordii. Studies have shown that triptolide exerts organ-protective effects. However, it remains unknown whether triptolide improves Alzheimer's disease (AD)-like presentations. Thirty healthy 8-week-old male C57BL/6J mice were randomly divided into control (n = 10), model (n = 10), and triptolide (n = 10) groups. Amyloid-β (Aβ)42 was injected bilaterally into the ventricles of mice in the model group. Triptolide was injected intraperitoneally daily after injecting Aβ42 (a total of 30 days) in the triptolide group. Learning and memory were tested using the Morris water maze test. The deposition of Aβ42 in the hippocampus was detected using immunohistochemical staining. In the hippocampus, three synaptic-associated proteins-gephyrin, collybistin, and GABRA1 -were detected by western blotting. Furthermore, we used ELISA to detect proinflammatory cytokines, including TNF-α and IL-1β, in the blood and hippocampus. Moreover, superoxide dismutase (SOD), malondialdehyde (MDA), and GSH levels were measured using the corresponding kits. We found that triptolide improved spatial learning and memory in AD-like mice. Additionally, triptolide maintained the expression of gephyrin, collybistin, and GABRA1 and reduced Aβ in these mice. Additionally, triptolide reduced the expression of inflammatory cytokines and decreased oxidative damage in AD-like mice. Our study suggests that triptolide attenuates AD-like changes in the mouse brain.
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Affiliation(s)
- Rui Mao
- Department of Neurology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Shihao Xu
- Department of Neurology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Guangwen Sun
- Department of Neurology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, China
- Department of Neurology, Sinopharm Dongfeng General Hospital, Jinzhou Medical University Union Training Base, Jinzhou, China
| | - Yingying Yu
- Department of Neurology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, China
- Department of Neurology, Sinopharm Dongfeng General Hospital, Jinzhou Medical University Union Training Base, Jinzhou, China
| | - Zhiyi Zuo
- Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Yuanyuan Wang
- Department of Neurology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Kun Yang
- Department of Anesthesiology, Sinopharm Dongfeng General Hospital, Jinzhou Medical University Union Training Base, Jinzhou, China
| | - Zhen Zhang
- Department of Orthopedics, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Wenqiong Yang
- Department of Neurology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, China
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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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35
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Neumann KD, Seshadri V, Thompson XD, Broshek DK, Druzgal J, Massey JC, Newman B, Reyes J, Simpson SR, McCauley KS, Patrie J, Stone JR, Kundu BK, Resch JE. Microglial activation persists beyond clinical recovery following sport concussion in collegiate athletes. Front Neurol 2023; 14:1127708. [PMID: 37034078 PMCID: PMC10080132 DOI: 10.3389/fneur.2023.1127708] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/06/2023] [Indexed: 04/11/2023] Open
Abstract
Introduction In concussion, clinical and physiological recovery are increasingly recognized as diverging definitions. This study investigated whether central microglial activation persisted in participants with concussion after receiving an unrestricted return-to-play (uRTP) designation using [18F]DPA-714 PET, an in vivo marker of microglia activation. Methods Eight (5 M, 3 F) current athletes with concussion (Group 1) and 10 (5 M, 5 F) healthy collegiate students (Group 2) were enrolled. Group 1 completed a pre-injury (Visit1) screen, follow-up Visit2 within 24 h of a concussion diagnosis, and Visit3 at the time of uRTP. Healthy participants only completed assessments at Visit2 and Visit3. At Visit2, all participants completed a multidimensional battery of tests followed by a blood draw to determine genotype and study inclusion. At Visit3, participants completed a clinical battery of tests, brain MRI, and brain PET; no imaging tests were performed outside of Visit3. Results For Group 1, significant differences were observed between Visits 1 and 2 (p < 0.05) in ImPACT, SCAT5 and SOT performance, but not between Visit1 and Visit3 for standard clinical measures (all p > 0.05), reflecting clinical recovery. Despite achieving clinical recovery, PET imaging at Visit3 revealed consistently higher [18F]DPA-714 tracer distribution volume (VT) of Group 1 compared to Group 2 in 10 brain regions (p < 0.001) analyzed from 164 regions of the whole brain, most notably within the limbic system, dorsal striatum, and medial temporal lobe. No notable differences were observed between clinical measures and VT between Group 1 and Group 2 at Visit3. Discussion Our study is the first to demonstrate persisting microglial activation in active collegiate athletes who were diagnosed with a sport concussion and cleared for uRTP based on a clinical recovery.
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Affiliation(s)
- Kiel D Neumann
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, United States
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
| | - Vikram Seshadri
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
| | - Xavier D Thompson
- Department of Kinesiology, University of Virginia, Charlottesville, VA, United States
| | - Donna K Broshek
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, United States
| | - Jason Druzgal
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
| | - James C Massey
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
| | - Benjamin Newman
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
| | - Jose Reyes
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
| | - Spenser R Simpson
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Katelyenn S McCauley
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
| | - James Patrie
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, United States
| | - James R Stone
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, United States
| | - Bijoy K Kundu
- Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
| | - Jacob E Resch
- Department of Kinesiology, University of Virginia, Charlottesville, VA, United States
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Javed H, Fizur NMM, Jha NK, Ashraf GM, Ojha S. Neuroprotective Potential and Underlying Pharmacological Mechanism of Carvacrol for Alzheimer's and Parkinson's Diseases. Curr Neuropharmacol 2023; 21:1421-1432. [PMID: 36567278 PMCID: PMC10324337 DOI: 10.2174/1570159x21666221223120251] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 12/27/2022] Open
Abstract
The phytochemicals have antioxidant properties to counter the deleterious effects of oxidative stress in the central nervous system and can be a promising drug candidate for neurodegenerative diseases. Among various phytochemicals, constituents of spice origin have recently received special attention for neurodegenerative diseases owing to their health benefits, therapeutic potential, edible nature, and dietary accessibility and availability. Carvacrol, a phenolic monoterpenoid, has garnered attention in treating and managing various human diseases. It possesses diverse pharmacological effects, including antioxidant, anti-inflammatory, antimicrobial and anticancer. Alzheimer's disease (AD) and Parkinson's disease (PD) are major public health concerns that place a significant financial burden on healthcare systems worldwide. The global burden of these diseases is expected to increase in the next few decades owing to increasing life expectancies. Currently, there is no cure for neurodegenerative diseases, such as AD and PD, and the available drugs only give symptomatic relief. For a long time, oxidative stress has been recognized as a primary contributor to neurodegeneration. Carvacrol enhances memory and cognition by modulating the effects of oxidative stress, inflammation, and Aβ25-35- induced neurotoxicity in AD. Moreover, it also reduces the production of reactive oxygen species and proinflammatory cytokine levels in PD, which further prevents the loss of dopaminergic neurons in the substantia nigra and improves motor functions. This review highlights carvacrol's potential antioxidant and anti-inflammatory properties in managing and treating AD and PD.
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Affiliation(s)
- Hayate Javed
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Nagoor Meeran Mohamed Fizur
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, UP, 201310, India
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India
| | - Ghulam Md. Ashraf
- Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
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Ghazimoradi MM, Ghoushi E, Ghobadi Pour M, Karimi Ahmadabadi H, Rafieian-Kopaei M. A Review on Garlic as a Supplement for Alzheimer’s Disease: A Mechanistic Insight into its Direct and Indirect Effects. Curr Pharm Des 2023; 29:519-526. [PMID: 36809972 DOI: 10.2174/1381612829666230222093016] [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: 07/29/2022] [Revised: 12/19/2022] [Accepted: 12/29/2022] [Indexed: 02/24/2023]
Abstract
Alzheimer’s disease (AD) is one of the most complicated neurodegenerative diseases causing dementia in human beings. Aside from that, the incidence of AD is increasing and its treatment is very complicated. There are several known hypotheses regarding the pathology of Alzheimer’s disease, including the amyloid beta hypothesis, tau hypothesis, inflammation hypothesis, and cholinergic hypothesis, which are investigated in different researches to completely elucidate the pathology of AD. Besides, some new mechanisms, such as immune, endocrine, and vagus pathways, as well as bacteria metabolite secretions, are being explained as other causes to be somehow related to AD pathogenesis. There is still no definite treatment for Alzheimer’s disease that can completely cure and eradicate AD. Garlic (Allium sativum) is a traditional herb used as a spice in different cultures, and due to the organosulfur compounds, like allicin, it possesses highly anti-oxidant properties; the benefits of garlic in cardiovascular diseases, like hypertension and atherosclerosis, have been examined and reviewed, although its beneficiary effects in neurodegenerative diseases, such as AD, are not completely understood. In this review, we discuss the effects of garlic based on its components, such as allicin and S-allyl cysteine, on Alzheimer’s disease and the mechanisms of garlic components that can be beneficiary for AD patients, including its effects on amyloid beta, oxidative stress, tau protein, gene expression, and cholinesterase enzymes. Based on the literature review, garlic has been revealed to have beneficiary effects on Alzheimer’s disease, especially in animal studies; however, more studies should be done on humans to find the exact mechanisms of garlic’s effects on AD patients.
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Affiliation(s)
- Mohammad Mahdi Ghazimoradi
- Faculty of pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Interdisciplinary Neuro-Brain Research and Education Network (INBREN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Ehsan Ghoushi
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Mozhgan Ghobadi Pour
- Department of Physiology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Mahmoud Rafieian-Kopaei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Nainu F, Mamada SS, Harapan H, Emran TB. Inflammation-Mediated Responses in the Development of Neurodegenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1411:39-70. [PMID: 36949305 DOI: 10.1007/978-981-19-7376-5_3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Since its first description over a century ago, neurodegenerative diseases (NDDs) have impaired the lives of millions of people worldwide. As one of the major threats to human health, NDDs are characterized by progressive loss of neuronal structure and function, leading to the impaired function of the CNS. While the precise mechanisms underlying the emergence of NDDs remains elusive, association of neuroinflammation with the emergence of NDDs has been suggested. The immune system is tightly controlled to maintain homeostatic milieu and failure in doing so has been shown catastrophic. Here, we review current concepts on the cellular and molecular drivers responsible in the induction of neuroinflammation and how such event further promotes neuronal damage leading to neurodegeneration. Experimental data generated from cell culture and animal studies, gross and molecular pathologies of human CNS samples, and genome-wide association study are discussed to provide deeper insights into the mechanistic details of neuroinflammation and its roles in the emergence of NDDs.
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Affiliation(s)
- Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Sukamto S Mamada
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Harapan Harapan
- School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
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Rejc L, Gómez-Vallejo V, Joya A, Arsequell G, Egimendia A, Castellnou P, Ríos-Anglada X, Cossío U, Baz Z, Iglesias L, Capetillo-Zarate E, Ramos-Cabrer P, Martin A, Llop J. Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography. Alzheimers Res Ther 2022; 14:80. [PMID: 35676734 PMCID: PMC9178858 DOI: 10.1186/s13195-022-01016-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 05/11/2022] [Indexed: 11/30/2022]
Abstract
Background Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter system (xc-), could be considered when assessing AD progression. Herein, we report the longitudinal investigation of [18F]DPA-714 and [18F]FSPG for their ability to detect TSPO and xc- biomarkers, respectively, in the 5xFAD mouse model for AD. Methods Expression of TSPO and xc- system was assessed longitudinally (2–12 months of age) on 5xFAD mice and their respective controls by positron emission tomography (PET) imaging using radioligands [18F]DPA-714 and [18F]FSPG. In parallel, in the same mice, amyloid-β plaque deposition was assessed with the amyloid PET radiotracer [18F]florbetaben. In vivo findings were correlated to ex vivo immunofluorescence staining of TSPO and xc- in microglia/macrophages and astrocytes on brain slices. Physiological changes of the brain tissue were assessed by magnetic resonance imaging (MRI) in 12-month-old mice. Results PET studies showed a significant increase in the uptake of [18F]DPA-714 and [18F]FSPG in the cortex, hippocampus, and thalamus in 5xFAD but not in WT mice over time. The results correlate with Aβ plaque deposition. Ex vivo staining confirmed higher TSPO overexpression in both, microglia/macrophages and astrocytes, and overexpression of xc- in non-glial cells of 5xFAD mice. Additionally, the results show that Aβ plaques were surrounded by microglia/macrophages overexpressing TSPO. MRI studies showed significant tissue shrinkage and microstructural alterations in 5xFAD mice compared to controls. Conclusions TSPO and xc- overexpression can be assessed by [18F]DPA-714 and [18F]FSPG, respectively, and correlate with the level of Aβ plaque deposition obtained with a PET amyloid tracer. These results position the two tracers as promising imaging tools for the evaluation of disease progression. Graphical abstract Longitudinal in vivo study in the 5xFAD mouse model shows that TSPO and oxidative stress assessment through [18F]DPA-714 and [18F]FSPG-PET imaging, respectively, could serve as a potential tool for the evaluation of Alzheimer disease progression. ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13195-022-01016-5.
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Russo C, Valle MS, Russo A, Malaguarnera L. The Interplay between Ghrelin and Microglia in Neuroinflammation: Implications for Obesity and Neurodegenerative Diseases. Int J Mol Sci 2022; 23:ijms232113432. [PMID: 36362220 PMCID: PMC9654207 DOI: 10.3390/ijms232113432] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
Abstract
Numerous studies have shown that microglia are capable of producing a wide range of chemokines to promote inflammatory processes within the central nervous system (CNS). These cells share many phenotypical and functional characteristics with macrophages, suggesting that microglia participate in innate immune responses in the brain. Neuroinflammation induces neurometabolic alterations and increases in energy consumption. Microglia may constitute an important therapeutic target in neuroinflammation. Recent research has attempted to clarify the role of Ghre signaling in microglia on the regulation of energy balance, obesity, neuroinflammation and the occurrence of neurodegenerative diseases. These studies strongly suggest that Ghre modulates microglia activity and thus affects the pathophysiology of neurodegenerative diseases. This review aims to summarize what is known from the current literature on the way in which Ghre modulates microglial activity during neuroinflammation and their impact on neurometabolic alterations in neurodegenerative diseases. Understanding the role of Ghre in microglial activation/inhibition regulation could provide promising strategies for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.
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Affiliation(s)
- Cristina Russo
- Section of Pathology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy
| | - Maria Stella Valle
- Laboratory of Neuro-Biomechanics, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Antonella Russo
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
| | - Lucia Malaguarnera
- Section of Pathology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy
- Correspondence:
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Pérot JB, Célestine M, Palombo M, Dhenain M, Humbert S, Brouillet E, Flament J. Longitudinal multimodal MRI characterization of a knock-in mouse model of Huntington's disease reveals early gray and white matter alterations. Hum Mol Genet 2022; 31:3581-3596. [PMID: 35147158 PMCID: PMC9616570 DOI: 10.1093/hmg/ddac036] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 01/19/2022] [Accepted: 01/31/2022] [Indexed: 11/24/2022] Open
Abstract
Pathogenesis of the inherited neurodegenerative disorder Huntington's disease (HD) is progressive with a long presymptomatic phase in which subtle changes occur up to 15 years before the onset of symptoms. Thus, there is a need for early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. Recent studies have shown that white matter may be affected early in mutant HTT gene carriers. A previous study performed on 12 months old Ki140CAG mice showed reduced glutamate level measured by Chemical Exchange Saturation Transfer of glutamate (gluCEST), especially in the corpus callosum. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, diffusion tensor imaging, gluCEST and magnetization transfer imaging, in order to assess white matter integrity over the life of this mouse model characterized by slow progression of symptoms. Our results show early defects of diffusion properties in the anterior part of the corpus callosum at 5 months of age, preceding gluCEST defects in the same region at 8 and 12 months that spread to adjacent regions. At 12 months, frontal and piriform cortices showed reduced gluCEST, as well as the pallidum. MT imaging showed reduced signal in the septum at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the potential role of white matter in the brain dysfunction that characterizes HD and the pertinence of gluCEST and DTI as biomarkers in HD.
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Affiliation(s)
- Jean-Baptiste Pérot
- Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center (MIRCen), Université Paris-Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Fontenay -aux-Roses 92260, France
| | - Marina Célestine
- Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center (MIRCen), Université Paris-Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Fontenay -aux-Roses 92260, France
| | - Marco Palombo
- Department of Computer Science, Centre for Medical Image Computing, University College London, London WC1E 6BT, UK
| | - Marc Dhenain
- Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center (MIRCen), Université Paris-Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Fontenay -aux-Roses 92260, France
| | - Sandrine Humbert
- Université Grenoble Alpes, INSERM, U1216, Grenoble Institut Neurosciences, Grenoble 38000 , France
| | - Emmanuel Brouillet
- Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center (MIRCen), Université Paris-Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Fontenay -aux-Roses 92260, France
| | - Julien Flament
- Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center (MIRCen), Université Paris-Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Fontenay -aux-Roses 92260, France
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Spatio-temporal metabolic rewiring in the brain of TgF344-AD rat model of Alzheimer's disease. Sci Rep 2022; 12:16958. [PMID: 36216838 PMCID: PMC9550832 DOI: 10.1038/s41598-022-20962-6] [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: 05/10/2022] [Accepted: 09/21/2022] [Indexed: 12/29/2022] Open
Abstract
Brain damage associated with Alzheimer's disease (AD) occurs even decades before the symptomatic onset, raising the need to investigate its progression from prodromal stages. In this context, animal models that progressively display AD pathological hallmarks (e.g. TgF344-AD) become crucial. Translational technologies, such as magnetic resonance spectroscopy (MRS), enable the longitudinal metabolic characterization of this disease. However, an integrative approach is required to unravel the complex metabolic changes underlying AD progression, from early to advanced stages. TgF344-AD and wild-type (WT) rats were studied in vivo on a 7 Tesla MRI scanner, for longitudinal quantitative assessment of brain metabolic profile changes using MRS. Disease progression was investigated at 4 time points, from 9 to 18 months of age, and in 4 regions: cortex, hippocampus, striatum, and thalamus. Compared to WT, TgF344-AD rats replicated common findings in AD patients, including decreased N-acetylaspartate in the cortex, hippocampus and thalamus, and decreased glutamate in the thalamus and striatum. Different longitudinal evolution of metabolic concentration was observed between TgF344-AD and WT groups. Namely, age-dependent trajectories differed between groups for creatine in the cortex and thalamus and for taurine in cortex, with significant decreases in Tg344-AD animals; whereas myo-inositol in the thalamus and striatum showed greater increase along time in the WT group. Additional analysis revealed divergent intra- and inter-regional metabolic coupling in each group. Thus, in cortex, strong couplings of N-acetylaspartate and creatine with myo-inositol in WT, but with taurine in TgF344-AD rats were observed; whereas in the hippocampus, myo-inositol, taurine and choline compounds levels were highly correlated in WT but not in TgF344-AD animals. Furthermore, specific cortex-hippocampus-striatum metabolic crosstalks were found for taurine levels in the WT group but for myo-inositol levels in the TgF344-AD rats. With a systems biology perspective of metabolic changes in AD pathology, our results shed light into the complex spatio-temporal metabolic rewiring in this disease, reported here for the first time. Age- and tissue-dependent imbalances between myo-inositol, taurine and other metabolites, such as creatine, unveil their role in disease progression, while pointing to the inadequacy of the latter as an internal reference for quantification.
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Ellagic Acid and Its Anti-Aging Effects on Central Nervous System. Int J Mol Sci 2022; 23:ijms231810937. [PMID: 36142849 PMCID: PMC9502104 DOI: 10.3390/ijms231810937] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/09/2022] [Accepted: 09/10/2022] [Indexed: 11/25/2022] Open
Abstract
Aging is an unavoidable biological process that leads to the decline of human function and the reduction in people’s quality of life. Demand for anti-aging medicines has become very urgent. Many studies have shown that ellagic acid (EA), a phenolic compound widely distributed in dicotyledonous plants, has powerful anti-inflammation and antioxidant properties. Moreover, it has been demonstrated that EA can enhance neuronal viability, reduce neuronal defects, and alleviate damage in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and cerebral ischemia. This paper reviews the biochemical functions and neuroprotective effects of EA, showing the clinical value of its application.
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Bilateral intracerebroventricular injection of streptozotocin induces AD-like behavioral impairments and neuropathological features in mice: Involved with the fundamental role of neuroinflammation. Biomed Pharmacother 2022; 153:113375. [PMID: 35834993 DOI: 10.1016/j.biopha.2022.113375] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/17/2022] [Accepted: 07/06/2022] [Indexed: 01/31/2023] Open
Abstract
OBJECTIVE To establish an Alzheimer's disease (AD) mouse model, investigate the behavioral performance changes and intracerebral molecular changes induced by bilateral intracerebroventricular injection of streptozotocin (STZ/I.C.V), and explore the potential pathogenesis of AD. METHODS An AD mouse model was established by STZ/I.C.V. The behavioral performance was observed via the open field test (OFT), novel object recognition test (NOR), and tail suspension test (TST). The mRNA and protein expressions of interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) in the hippocampus were measured via qPCR and Western blot. The expression of β-amyloid 1-42 (Aβ1-42), phosphorylated Tau protein (p-Tau (Ser396)), Tau5, β-site amyloid precursor protein (APP) cleaving enzyme (BACE), insulin receptor substrate 1 (IRS1), brain-derived neurotrophic factor (BDNF), Copine6, synaptotagmin-1 (Syt-1), synapsin-1, phosphoinositol 3 kinase (PI3K), serine/threonine kinase (Akt), phosphorylated serine/threonine kinase (p-Akt (Ser473)), triggering receptor expressed on myeloid cells-1/2 (TREM1/2) were detected using Western blot, and the expression of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (IBA1), Aβ1-42, p-Tau(Ser396), Syt-1, BDNF were measured via immunofluorescence staining. RESULTS STZ/I.C.V induced AD-like neuropsychiatric behaviors in mice, as indicated by the impairment of learning and memory, together with the reduced spontaneous movement and exploratory behavior. The expression of BACE, Aβ1-42, p-Tau(Ser396), and TREM2 were significantly increased in the hippocampus of model mice, while the expression of IRS1, BDNF, Copine6, Syt-1, synapsin-1, PI3K, p-Akt(Ser473), and TREM1 were decreased as compared with that of the controls. Furthermore, the model mice presented a hyperactivation of astrocytes and microglia in the hippocampus, accompanied by the increased mRNA and protein expressions of IL-1β, IL-6 and TNF-α. CONCLUSION STZ/I.C.V is an effective way to induce AD mice model, with not only AD-like neuropsychiatric behaviors, but also typic AD-like neuropathological features including neurofibrillary tangles, deposit of β-amyloid (Aβ), neuroinflammation, and imbalanced synaptic plasticity.
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Yang M, Wang J. Berberine Ameliorates Cognitive Disorder via GSK3β/PGC-1α Signaling in APP/PS1 Mice. J Nutr Sci Vitaminol (Tokyo) 2022; 68:228-235. [PMID: 35768254 DOI: 10.3177/jnsv.68.228] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Previous studies have revealed that Berberine (BBR) had therapeutic effects on Alzheimer's disease (AD). However, the underlying mechanism of BBR in the treatment of AD is unclear. The study was to investigate whether berberine ameliorates cognitive disorder in AD by regulating on GSK3β/PGC-1α signaling pathway. APP/PS1 mice were treated with BBR (50 mg/kg and 100 mg/kg) for 4 mo, and the cognitive function of mice was tested by Morris water maze. The levels of inflammatory cytokines IL-1β, TNF-α, and IL-6 in hippocampus of mice were detected by ELISA kits. The damage of neuronal in hippocampal CA1 was detected by Nissl staining. The tau and GSK3β protein were detected by western blot. The results showed that BBR treatment obviously improved spatial cognitive function of APP/PS1 mice. Meanwhile, the pro-inflammatory cytokines were decreased in hippocampus by the administration of BBR. Additionally, BBR significantly alleviated neuronal damage and reduced the levels of hyperphosphorylated tau at sites of Thr205 and Thr231 in hippocampus. Importantly, BBR inhibited the activity of GSK3β and increased the expression of PGC-1α. Consequently, our results demonstrates that BBR could improve the cognitive function by inhibiting the tau hyperphosphorylation and neuroinflammation. These beneficial effects of BBR may be attributed to the regulation of GSK3β/PGC-1α signaling pathway in APP/PS1 mice. These findings reveal a vital role for GSK3β/PGC-1α signaling pathway in retarding cognitive disorder, indicating that PGC-1α might be a potential target for the treatment of AD.
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Affiliation(s)
- Meng Yang
- College of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College
| | - Jing Wang
- College of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College
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Sriram S, Mehkri Y, Quintin S, Lucke-Wold B. Shared pathophysiology: Understanding stroke and Alzheimer's disease. Clin Neurol Neurosurg 2022; 218:107306. [PMID: 35636382 DOI: 10.1016/j.clineuro.2022.107306] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/03/2022] [Accepted: 05/19/2022] [Indexed: 12/17/2022]
Abstract
Alzheimer's disease and stroke share several known vascular risk factors. The pathophysiology and whether one predisposes to the other is a topic of ongoing investigation. In this critical review, we highlight what is known about each pathway and the shared potential mechanisms. We offer insight into topics that warrant further investigation. We address topics of both neurodegeneration and secondary cascades. Furthermore, the concept of targeting secondary mechanisms early might be a viable treatment option for ongoing preventative measures. The review is intended to serve as a catalyst for further scientific inquiry into this important topic.
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Affiliation(s)
- Sai Sriram
- Department of Neurosurgery, University of Florida, Gainesville, USA
| | - Yusuf Mehkri
- Department of Neurosurgery, University of Florida, Gainesville, USA
| | - Stephan Quintin
- Department of Neurosurgery, University of Florida, Gainesville, USA
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Bai R, Guo J, Ye XY, Xie Y, Xie T. Oxidative stress: The core pathogenesis and mechanism of Alzheimer's disease. Ageing Res Rev 2022; 77:101619. [PMID: 35395415 DOI: 10.1016/j.arr.2022.101619] [Citation(s) in RCA: 317] [Impact Index Per Article: 105.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 03/21/2022] [Accepted: 04/02/2022] [Indexed: 02/07/2023]
Abstract
As the number of patients with Alzheimer's disease (AD) increases, it brings great suffering to their families and causes a heavy socioeconomic burden to society. A vast amount of funds and a mass of research have been devoted to elucidating the pathology of AD. However, the main pathogenesis is still elusive, and its mechanism is not completely clear. Research on the mechanisms of AD mainly focuses on the amyloid cascade, tau protein, neuroinflammation, metal ions, and oxidative stress hypotheses. Oxidative stress is as a bridge that connects the different hypotheses and mechanisms of AD. It is a process that causes neuronal damage and occurs in various pathways. Oxidative stress plays a critical role in AD and can even be considered a crucial central factor in the pathogenesis of AD. Previous reviews have also summarized the role of oxidative stress in AD, but these mainly review a specific signaling pathway. Taking oxidative stress as the central point, this review comprehensively expands on the roles of oxidative stress that are involved in the pathogenesis of AD. The vivid and easy-to-understand figures systematically clarify the connected roles of oxidative stress in AD and allow readers to further understand oxidative stress and AD.
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Affiliation(s)
- Renren Bai
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou 311121, PR China.
| | - Jianan Guo
- College of Pharmaceutical Science, Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China
| | - Xiang-Yang Ye
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Yuanyuan Xie
- College of Pharmaceutical Science, Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China.
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou 311121, PR China.
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Chai W, Zhang J, Xiang Z, Zhang H, Mei Z, Nie H, Xu R, Zhang P. Potential of nobiletin against Alzheimer's disease through inhibiting neuroinflammation. Metab Brain Dis 2022; 37:1145-1154. [PMID: 35267136 DOI: 10.1007/s11011-022-00932-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 02/07/2022] [Indexed: 12/31/2022]
Abstract
OBJECTIVE This study aimed to explore the mechanism of Nobiletin attenuating Alzheimer's disease (AD) by inhibiting neuroinflammation. METHODS The expression of inflammatory cytokines and HMGB-1 in serum of AD patients were examined. Microglia (MGs) were treated with different doses of Nobiletin before LPS and Nigericin induction. Cell viability and apoptosis were determined by CCK-8 and TUNEL assays, respectively. APP/PS1 mice were gavaged with Nobiletin, and Morris water maze (MWM) was established to record swimming speed, escape latency, the number of platform crossings, and time spent in the platform quadrant. MGs activation in brain tissues was evaluated by immunofluorescence. The expression of pyroptosis-related proteins, inflammatory cytokines, and HMGB-1 was determined in the hippocampus and MGs. RESULTS The levels of inflammatory cytokines and HMGB-1 were high in serum of AD patients. Treatment with different concentrations of Nobiletin prominently enhanced cell viability and reduced apoptosis and the expression of inflammatory cytokine and pyroptosis-related proteins in LPS + Nigericin-induced MGs. Gavage of different doses of Nobiletin into APP/PS1 mice shortened the escape latency in mice, diminished MGs activation in brain tissues, and remarkably elevated the number of platform crossings and the time spent in the platform quadrant without obvious change in swimming speed, suggesting that Nobiletin improved the spatial learning and memory abilities in APP/PS1 mice. The expression of pyroptosis-related proteins, HMGB-1, and inflammatory cytokines was decreased dramatically by Nobiletin in the hippocampus of APP/PS1 mice. CONCLUSIONS Nobiletin can inhibit neuroinflammation by inhibiting HMGB-1, pyroptosis-related proteins, and inflammatory cytokines, thus mitigating AD.
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Affiliation(s)
- Wen Chai
- Department of Neurology, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, No.152, Aiguo Road, 330006, Nanchang, Jiangxi, P.R. China
| | - Ji Zhang
- Department of Neurology, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, No.152, Aiguo Road, 330006, Nanchang, Jiangxi, P.R. China
| | - Zhengbing Xiang
- Department of Neurology, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, No.152, Aiguo Road, 330006, Nanchang, Jiangxi, P.R. China
| | - Honglian Zhang
- Department of Neurology, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, No.152, Aiguo Road, 330006, Nanchang, Jiangxi, P.R. China
| | - Zhujun Mei
- Department of Neurology, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, No.152, Aiguo Road, 330006, Nanchang, Jiangxi, P.R. China
| | - Hongbing Nie
- Department of Neurology, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, No.152, Aiguo Road, 330006, Nanchang, Jiangxi, P.R. China
| | - Renxu Xu
- Department of Neurology, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, No.152, Aiguo Road, 330006, Nanchang, Jiangxi, P.R. China
- Department of General Practice/General Family Medicine, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, 330006, Nanchang, Jiangxi, P.R. China
| | - Ping Zhang
- Department of Neurology, The First Affiliated Hospital of Nanchang Medical College/Jaingxi Provincial People's Hospital, No.152, Aiguo Road, 330006, Nanchang, Jiangxi, P.R. China.
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Feng T, Hu X, Fukui Y, Bian Z, Bian Y, Sun H, Takemoto M, Yunoki T, Nakano Y, Morihara R, Abe K, Yamashita T. Clinical and Pathological Benefits of Scallop-Derived Plasmalogen in a Novel Mouse Model of Alzheimer’s Disease with Chronic Cerebral Hypoperfusion. J Alzheimers Dis 2022; 86:1973-1982. [DOI: 10.3233/jad-215246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: The oral ingestion of scallop-derived plasmalogen (sPlas) significantly improved cognitive function in Alzheimer’s disease (AD) patients. Objective: However, the effects and mechanisms of sPlas on AD with chronic cerebral hypoperfusion (CCH), a class of mixed dementia contributing to 20–30% among the dementia society, were still elusive. Methods: In the present study, we applied a novel mouse model of AD with CCH to investigate the potential effects of sPlas on AD with CCH. Results: The present study demonstrated that sPlas significantly recovered cerebral blood flow, improved motor and cognitive deficits, reduced amyloid-β pathology, regulated neuroinflammation, ameliorated neural oxidative stress, and inhibited neuronal loss in AD with CCH mice at 12 M. Conclusion: These findings suggest that sPlas possesses clinical and pathological benefits for AD with CCH in the novel model mice. Furthermore, sPlas could have promising prevention and therapeutic effects on patients of AD with CCH.
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Affiliation(s)
- Tian Feng
- Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, China
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Xinran Hu
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yusuke Fukui
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Zhihong Bian
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuting Bian
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hongming Sun
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Mami Takemoto
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Taijun Yunoki
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yumiko Nakano
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Ryuta Morihara
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Koji Abe
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Toru Yamashita
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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Park G, Jeon SJ, Ko IO, Park JH, Lee KC, Kim MS, Shin CY, Kim H, Lee YS. Decreased in vivo glutamate/GABA ratio correlates with the social behavior deficit in a mouse model of autism spectrum disorder. Mol Brain 2022; 15:19. [PMID: 35183218 PMCID: PMC8858545 DOI: 10.1186/s13041-022-00904-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/08/2022] [Indexed: 12/29/2022] Open
Abstract
To diagnose autism spectrum disorder (ASD), researchers have sought biomarkers whose alterations correlate with the susceptibility to ASD. However, biomarkers closely related to the pathophysiology of ASD are lacking. Even though excitation/inhibition (E/I) imbalance has been suggested as an underlying mechanism of ASD, few studies have investigated the actual ratio of glutamate (Glu) to γ-aminobutyric acid (GABA) concentration in vivo. Moreover, there are controversies in the directions of E/I ratio alterations even in extensively studied ASD animal models. Here, using proton magnetic resonance spectroscopy (1H-MRS) at 9.4T, we found significant differences in the levels of different metabolites or their ratios in the prefrontal cortex and hippocampus of Cntnap2−/− mice compared to their wild-type littermates. The Glu/GABA ratio, N-acetylaspartate (NAA)/total creatine (tCr) ratio, and tCr level in the prefrontal cortex were significantly different in Cntnap2−/− mice compared to those in wild-type mice, and they significantly correlated with the sociability of mice. Moreover, receiver operating characteristic (ROC) analyses indicated high specificity and selectivity of these metabolites in discriminating genotypes. These results suggest that the lowered Glu/GABA ratio in the prefrontal cortex along with the changes in the other metabolites might contribute to the social behavior deficit in Cntnap2−/− mice. Our results also demonstrate the utility of 1H-MRS in investigating the underlying mechanisms or the diagnosis of ASD.
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