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Cao T, Liao P, Lu J, Liang G, Wei Q, Song W, Lan Y, Zeng J, Zou C, Pan M, Su L, Zou D. Single-nucleus RNA sequencing and network pharmacology reveal the mediation of fisetin on neuroinflammation in Alzheimer's disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156724. [PMID: 40215814 DOI: 10.1016/j.phymed.2025.156724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/20/2025] [Accepted: 04/01/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive function and memory. This study explores cellular subgroups in AD using single-nucleus RNA sequencing (snRNA-seq). It integrates the pharmacological network of traditional Chinese medicine (TCM) to identify potential therapeutic targets, providing a theoretical basis for the development of clinical AD. METHODS We obtained data information from the Gene Expression Omnibus (GEO) for snRNA-seq analysis. Enrichment and pseudotime analysis were performed to explore the functions and differentiation pathways of cellular subgroups. Cellular communication networks were mapped to reveal subgroup interactions. Additionally, a pharmacological network for AD was constructed using the TCM pharmacology database. RESULTS We identified several cell subgroups associated with AD pathology, contributing to disease progression in various ways. Notably, the TNC+ CD44+ astrocyte subgroup activated the I-kappa B kinase/ NF-κB signaling pathway, leading to increased expression of inflammatory cytokines. In the pharmacological network, fisetin was identified as a promising compound with the potential to bind to the CD44 protein, mitigating the inflammatory response and preventing further neuronal damage. CONCLUSIONS By exploring the ecological landscape of various cellular subgroups in AD and investigating the roles and mechanisms, combined with molecular docking and pharmacological network screening, our findings provide new insights and therapeutic possibilities for AD treatment.
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Affiliation(s)
- Tingting Cao
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China
| | - Peiling Liao
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China; Department of Neurology, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Jia Lu
- School of Basic Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Guining Liang
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China
| | - Qingyan Wei
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China
| | - Wenyi Song
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China
| | - Yating Lan
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China
| | - Jingyi Zeng
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China
| | - Chun Zou
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China
| | - Mika Pan
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China
| | - Li Su
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China; Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Baise, Guangxi 533000, China.
| | - Donghua Zou
- Department of Neurology, The Second Affiliated Hospital of Guangxi Medical University, Nannning, Guangxi 530007, China.
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Xu Y, Zhang H, Jiao X, Zhang Y, Yin G, Wang C, Du Z, Liang M, Gao X, Gu Z, Jiang Y, Du B, Bi X. Dysregulations of C1QA, C1QB, C1QC and C5AR1 as candidate biomarkers of vascular dementia. NPJ AGING 2025; 11:42. [PMID: 40414977 DOI: 10.1038/s41514-025-00228-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 04/22/2025] [Indexed: 05/27/2025]
Abstract
Vascular dementia (VaD) is the second most common cause of dementia. Few bioinformatic analysis has been done to explore its biomarkers. This study aimed to excavate potential biomarkers for VaD using bioinformatic analysis and validate them at both animal and patient levels. Based on microarray data of GSE122063, bioinformatic analysis revealed 502 DEGs in the frontal and 674 DEGs in the temporal cortex of VaD patients. Afterward, the hub genes between two regions, including C1QA, C1QB, C1QC, and C5AR1, were dugout. Interestingly, compared with sham mice or controls, the above four complements were highly expressed in the cortices of VaD animals and in the peripheral serum of VaD patients. Moreover, receiver operating characteristic curve analysis conformed to good diagnostic powers of these complements, with C1QB having the most prominent capacity (AUC = 0.799, 95%CI 0.722-0.875). That means the complements, especially subunits of C1Q, might be used as specific early VaD diagnostic biomarkers.
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Affiliation(s)
- Yawen Xu
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
- Department of Neurology, Dalian Municipal Central Hospital Affiliated to Dalian University of Technology, Dalian, PR China
| | - Hailing Zhang
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Xuehao Jiao
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Yanbo Zhang
- Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Ge Yin
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Cui Wang
- Department of Neurology, Dalian Municipal Central Hospital Affiliated to Dalian University of Technology, Dalian, PR China
| | - Zengkan Du
- Faculty of Basic Medical Sciences, Second Military Medical University, Shanghai, PR China
| | - Meng Liang
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Xin Gao
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Zhengsheng Gu
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Yan Jiang
- School of Pharmacy, Second Military Medical University, Shanghai, PR China
- Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Bingying Du
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China.
- State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Disease, Fudan University, Shanghai, PR China.
| | - Xiaoying Bi
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China.
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Tenner AJ, Petrisko TJ. Knowing the enemy: strategic targeting of complement to treat Alzheimer disease. Nat Rev Neurol 2025; 21:250-264. [PMID: 40128350 DOI: 10.1038/s41582-025-01073-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2025] [Indexed: 03/26/2025]
Abstract
The complement system protects against infection, positively responds to tissue damage, clears cell debris, directs and modulates the adaptive immune system, and functions in neuronal development, normal synapse elimination and intracellular metabolism. However, complement also has a role in aberrant synaptic pruning and neuroinflammation - processes that lead to a feedforward loop of inflammation, injury and neuronal death that can contribute to neurodegenerative and neurological disorders, including Alzheimer disease. This Review provides justification, largely from preclinical mouse models but also from correlates with human tissue and biomarkers, for targeting specific complement components for therapeutic intervention in Alzheimer disease. We discuss promising strategies to slow the progression of cognitive loss with minimal undesired effects. The diverse interactions and functions of complement system components can influence biological processes in the healthy and diseased brain; here, these functions are described as a prerequisite to selecting appropriate, safe and effective therapeutic targets for translation to the clinic.
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Affiliation(s)
- Andrea J Tenner
- Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA, USA.
- Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.
- Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
| | - Tiffany J Petrisko
- Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA, USA
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Lin YJ, Liu Y, Sheng ZH, Fu Y, Ma LZ, Zhang ZH, Wang LY, Huang LY, Liu M, Wang ZT, Tan L. The associations of cerebrospinal fluid ApoE and C1q with Alzheimer's disease biomarkers. J Alzheimers Dis 2025; 104:852-861. [PMID: 40091552 DOI: 10.1177/13872877251320419] [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: 03/19/2025]
Abstract
BackgroundThe roles of complement 1q (C1q) and Apolipoprotein E (ApoE) in driving Alzheimer's disease (AD) progression might be explained by their associations with neuroinflammation and AD pathology which were previously reported.ObjectiveWe examined the associations of cerebrospinal fluid (CSF) C1q and ApoE with CSF neuroinflammatory biomarkers and AD core biomarkers, as well as explored whether C1q mediated the associations of CSF ApoE with these biomarkers.MethodsHere, we analyzed CSF proteomics data from Alzheimer's Disease Neuroimaging Initiative (ADNI) using two different ADNI proteomics datasets-SomaScan (n = 579)and multiple reaction monitoring (MRM[n = 207]). Linear regression analyses were conducted to explore the association of CSF ApoE and C1q. The mediation model and structural equation model (SEM) were conducted to explore the associations of ApoE and C1q with AD biomarkers.ResultsMultiple linear regression showed that CSF ApoE was positively associated with CSF C1q in total participants and Alzheimer's continuum participants. Mediation analyses indicated that C1q mediated the associations of CSF ApoE with CSF T-tau, P-tau, sTREM2 and GFAP (mediation proportions range from 15.06 to 44.64%; all the p values < 0.05) but not with CSF amyloid-β and progranulin (PGRN). The SEM yielded similar results.ConclusionsOur findings suggest that C1q is linked to ApoE, and it mediates the associations of ApoE with T-tau, P-tau, sTREM2, GFAP, indicating C1q association with ApoE might be involved in AD progression.
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Affiliation(s)
- Yu-Jing Lin
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
| | - Ying Liu
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Ze-Hu Sheng
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Yan Fu
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Ling-Zhi Ma
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Zi-Hao Zhang
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Lan-Yang Wang
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China
| | - Liang-Yu Huang
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Min Liu
- Department of Neurology, Qingdao Municipal Hospital, Dalian Medical University, Dalian, China
| | - Zuo-Teng Wang
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Lan Tan
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
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Ali A, Milman S, Weiss EF, Gao T, Napolioni V, Barzilai N, Zhang ZD, Lin J. Genetic variants associated with age-related episodic memory decline implicate distinct memory pathologies. Alzheimers Dement 2025; 21:e14379. [PMID: 39559945 PMCID: PMC11775541 DOI: 10.1002/alz.14379] [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: 05/10/2024] [Revised: 09/30/2024] [Accepted: 10/11/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Approximately 40% of people aged ≥ 65 experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes. METHODS We investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All-atom molecular dynamics simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline. RESULTS In addition to the common polygenic risk of Alzheimer's disease, we identified and replicated rare variant associations in ITSN1 and CRHR2. Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L-serine synthesis. DISCUSSION Our study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogenous memory pathologies mediated by rare coding variants. HIGHLIGHTS We demonstrated the contribution of the common polygenic risk of Alzheimer's disease to episodic memory decline. We discovered and replicated two risk genes associated with episodic memory decline implicated by rare variants, were discovered and replicated. We demonstrated molecular mechanisms and potential novel memory pathologies underlying interfacial rare coding variants. Molecular dynamics simulations were performed to understand the downstream effects of risk rare coding variants.
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Affiliation(s)
- Amanat Ali
- Department of MedicineAlbert Einstein College of MedicineBronxNew YorkUSA
| | - Sofiya Milman
- Department of MedicineAlbert Einstein College of MedicineBronxNew YorkUSA
- Department of GeneticsAlbert Einstein College of MedicineBronxNew YorkUSA
| | - Erica F. Weiss
- Department of NeurologyAlbert Einstein College of MedicineBronxNew YorkUSA
| | - Tina Gao
- Department of MedicineAlbert Einstein College of MedicineBronxNew YorkUSA
| | - Valerio Napolioni
- School of Biosciences and Veterinary MedicineUniversity of CamerinoCamerinoItaly
| | - Nir Barzilai
- Department of MedicineAlbert Einstein College of MedicineBronxNew YorkUSA
- Department of GeneticsAlbert Einstein College of MedicineBronxNew YorkUSA
| | - Zhengdong D. Zhang
- Department of GeneticsAlbert Einstein College of MedicineBronxNew YorkUSA
| | - Jhih‐Rong Lin
- Department of GeneticsAlbert Einstein College of MedicineBronxNew YorkUSA
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Patil N, Patil K, Jain M, Mohammed A, Yadav A, Dhanda PS, Kole C, Dave K, Kaushik P, Azhar Abdul Razab MK, Hamzah Z, Nawi NM. A systematic study of molecular targets of cannabidiol in Alzheimer's disease. J Alzheimers Dis Rep 2024; 8:1339-1360. [PMID: 40034365 PMCID: PMC11863746 DOI: 10.1177/25424823241284464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 08/27/2024] [Indexed: 03/05/2025] Open
Abstract
Background Alzheimer's disease (AD) is a prevalent, incurable, and chronic neurodegenerative condition characterized by the accumulation of amyloid-β protein (Aβ), disrupting various bodily systems. Despite the lack of a cure, phenolic compounds like cannabidiol (CBD), a non-psychoactive component of cannabis, have emerged as potential therapeutic agents for AD. Objective This systematic review explores the impact of different types of cannabidiol on AD, unveiling their neuroprotective mechanisms. Methods The research used PubMed, Scopus, and Web of Science databases with keywords like "Alzheimer's disease" and "Cannabidiol." Studies were evaluated based on title, abstract, and relevance to treating AD with CBD. No restrictions on research type or publication year. Excluded were hypothesis papers, reviews, books, unavailable articles, etc. Results Microsoft Excel identified 551 articles, with 92 included in the study, but only 22 were thoroughly evaluated. In-vivo and in-silico studies indicate that CBD may disrupt Aβ42, reduce pro-inflammatory molecule release, prevent reactive oxygen species formation, inhibit lipid oxidation, and counteract Aβ-induced increases in intracellular calcium, thereby protecting neurons from apoptosis. Conclusions In summary, the study indicates that CBD and its analogs reduce the production of Aβ42. Overall, these findings support the potential of CBD in alleviating the underlying pathology and symptoms associated with AD, underscoring the crucial need for further rigorous scientific investigation to elucidate the therapeutic applications and mechanisms of CBD in AD.
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Affiliation(s)
- Nil Patil
- Cell & Developmental Biology Lab, Research & Development Cell, Parul University, Vadodara, Gujarat, India
- Department of Life Sciences, Parul Institute of Applied Sciences, Parul University, Vadodara, Gujarat, India
| | - Khushalika Patil
- Department of Life Sciences, Parul Institute of Applied Sciences, Parul University, Vadodara, Gujarat, India
| | - Mukul Jain
- Cell & Developmental Biology Lab, Research & Development Cell, Parul University, Vadodara, Gujarat, India
- Department of Life Sciences, Parul Institute of Applied Sciences, Parul University, Vadodara, Gujarat, India
- Faculty of Earth Science, Universiti Malaysia Kelantan, Jeli, Kelantan, Malaysia
| | - Arifullah Mohammed
- Department of Agriculture Science, Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Jeli, Kelantan, Malaysia
| | - Alpa Yadav
- Department of Botany, Indra Gandhi University, Meerpur, Rewari, India
| | | | | | - Kirtan Dave
- Bioinformatics Laboratory, Research & Development Cell, Parul University, Vadodara, Gujarat, India
| | - Prashant Kaushik
- Chaudhary Charan Singh Haryana Agricultural University, Hisar, India
| | | | - Zulhazman Hamzah
- Faculty of Earth Science, Universiti Malaysia Kelantan, Jeli, Kelantan, Malaysia
| | - Norazlina Mat Nawi
- Department of Nuclear Medicine, Radiotherapy & Oncology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia
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West EE, Kemper C. Intracellular C1q - an unexpected player in neuronal proteostasis. Trends Immunol 2024; 45:718-720. [PMID: 39327206 DOI: 10.1016/j.it.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 09/14/2024] [Indexed: 09/28/2024]
Abstract
Extrahepatic, cell-autonomous, and/or intracellularly active complement components are increasingly recognized as key orchestrators of cell physiological processes. A recent study by Scott-Hewitt et al. demonstrates that microglia-derived C1q unexpectedly associates with the ribosomes of neurons in the aging murine brain, where it impacts protein translation and impairs the extinction of conditioned fear responses.
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Affiliation(s)
- Erin E West
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Claudia Kemper
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
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Ge TQ, Guan PP, Wang P. Complement 3a induces the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms during the development and progression of Alzheimer's disease. Neurosci Biobehav Rev 2024; 165:105868. [PMID: 39218048 DOI: 10.1016/j.neubiorev.2024.105868] [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: 05/10/2024] [Revised: 08/08/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
As a central molecule in complement system (CS), complement (C) 3 is upregulated in the patients and animal models of Alzheimer's disease (AD). C3 will metabolize to iC3b and C3a. iC3b is responsible for clearing β-amyloid protein (Aβ). In this scenario, C3 exerts neuroprotective effects against the disease via iC3b. However, C3a will inhibit microglia to clear the Aβ, leading to the deposition of Aβ and impair the functions of synapses. To their effects on AD, activation of C3a and C3a receptor (C3aR) will impair the mitochondria, leading to the release of reactive oxygen species (ROS), which activates the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes. The overloading of NLRP3 inflammasomes activate microglia, leading to the formation of inflammatory environment. The inflammatory environment will facilitate the deposition of Aβ and abnormal synapse pruning, which results in the progression of AD. Therefore, the current review will decipher the mechanisms of C3a inducing the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms, which facilitates the understanding the AD.
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Affiliation(s)
- Tong-Qi Ge
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, PR China; College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China
| | - Pei-Pei Guan
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
| | - Pu Wang
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, PR China.
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Serradas ML, Ding Y, Martorell PV, Kulińska I, Castro-Gomez S. Therapeutic Targets in Innate Immunity to Tackle Alzheimer's Disease. Cells 2024; 13:1426. [PMID: 39272998 PMCID: PMC11394242 DOI: 10.3390/cells13171426] [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: 07/30/2024] [Revised: 08/18/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
There is an urgent need for effective disease-modifying therapeutic interventions for Alzheimer's disease (AD)-the most prevalent cause of dementia with a profound socioeconomic burden. Most clinical trials targeting the classical hallmarks of this disease-β-amyloid plaques and neurofibrillary tangles-failed, showed discrete clinical effects, or were accompanied by concerning side effects. There has been an ongoing search for novel therapeutic targets. Neuroinflammation, now widely recognized as a hallmark of all neurodegenerative diseases, has been proven to be a major contributor to AD pathology. Here, we summarize the role of neuroinflammation in the pathogenesis and progression of AD and discuss potential targets such as microglia, TREM2, the complement system, inflammasomes, and cytosolic DNA sensors. We also present an overview of ongoing studies targeting specific innate immune system components, highlighting the progress in this field of drug research while bringing attention to the delicate nature of innate immune modulations in AD.
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Affiliation(s)
- Maria L. Serradas
- Institute of Physiology II, University Hospital Bonn, 53115 Bonn, Germany
| | - Yingying Ding
- Institute of Physiology II, University Hospital Bonn, 53115 Bonn, Germany
| | - Paula V. Martorell
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
| | - Ida Kulińska
- Institute of Physiology II, University Hospital Bonn, 53115 Bonn, Germany
| | - Sergio Castro-Gomez
- Institute of Physiology II, University Hospital Bonn, 53115 Bonn, Germany
- Center for Neurology, Department of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, 53127 Bonn, Germany
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Schartz ND, Liang HY, Carvalho K, Chu SH, Mendoza-Arvilla A, Petrisko TJ, Gomez-Arboledas A, Mortazavi A, Tenner AJ. C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model. Nat Commun 2024; 15:7028. [PMID: 39147742 PMCID: PMC11327341 DOI: 10.1038/s41467-024-51163-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 07/30/2024] [Indexed: 08/17/2024] Open
Abstract
Alzheimer's disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. The complement pathway has been proposed as a therapeutic target. C5aR1 inhibition reduces plaque load, gliosis, and memory deficits in animal models, however, the cellular bases underlying this neuroprotection were unclear. Here, we show that the C5aR1 antagonist PMX205 improves outcomes in the Arctic48 mouse model of AD. A combination of single cell and single nucleus RNA-seq analysis of hippocampi derived from males and females identified neurotoxic disease-associated microglia clusters in Arctic mice that are C5aR1-dependent, while microglial genes associated with synapse organization and transmission and learning were overrepresented in PMX205-treated mice. PMX205 also reduced neurotoxic astrocyte gene expression, but clusters associated with protective responses to injury were unchanged. C5aR1 inhibition promoted mRNA-predicted signaling pathways between brain cell types associated with cell growth and repair, while suppressing inflammatory pathways. Finally, although hippocampal plaque load was unaffected, PMX205 prevented deficits in short-term memory in female Arctic mice. In conclusion, C5aR1 inhibition prevents cognitive loss, limits detrimental glial polarization while permitting neuroprotective responses, as well as leaving most protective functions of complement intact, making C5aR1 antagonism an attractive therapeutic strategy for AD.
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Affiliation(s)
- Nicole D Schartz
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Heidi Y Liang
- Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - Klebea Carvalho
- Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - Shu-Hui Chu
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Adrian Mendoza-Arvilla
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Tiffany J Petrisko
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Angela Gomez-Arboledas
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Ali Mortazavi
- Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - Andrea J Tenner
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA.
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
- Department of Pathology and Laboratory Medicine, University of California, Irvine, School of Medicine, Irvine, CA, USA.
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Ali A, Milman S, Weiss EF, Gao T, Napolioni V, Barzilai N, Zhang ZD, Lin JR. Rare genetic coding variants associated with age-related episodic memory decline implicate distinct memory pathologies in the hippocampus. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.05.21.24307692. [PMID: 38826255 PMCID: PMC11142267 DOI: 10.1101/2024.05.21.24307692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Background Approximately 40% of people aged 65 or older experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes. Methods We investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All-atom MD simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline. Results In addition to the common polygenic risk of Alzheimer's Disease (AD), we identified and replicated rare variant association in ITSN1 and CRHR2 . Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L-serine synthesis. Discussion Our study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogeneous memory pathologies mediated by rare coding variants.
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Ayyubova G, Fazal N. Beneficial versus Detrimental Effects of Complement-Microglial Interactions in Alzheimer's Disease. Brain Sci 2024; 14:434. [PMID: 38790413 PMCID: PMC11119363 DOI: 10.3390/brainsci14050434] [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: 04/04/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/26/2024] Open
Abstract
Research indicates that brain-region-specific synapse loss and dysfunction are early hallmarks and stronger neurobiological correlates of cognitive decline in Alzheimer's disease (AD) than amyloid plaque and neurofibrillary tangle counts or neuronal loss. Even though the precise mechanisms underlying increased synaptic pruning in AD are still unknown, it has been confirmed that dysregulation of the balance between complement activation and inhibition is a crucial driver of its pathology. The complement includes three distinct activation mechanisms, with the activation products C3a and C5a, potent inflammatory effectors, and a membrane attack complex (MAC) leading to cell lysis. Besides pro-inflammatory cytokines, the dysregulated complement proteins released by activated microglia bind to amyloid β at the synaptic regions and cause the microglia to engulf the synapses. Additionally, research indicating that microglia-removed synapses are not always degenerating and that suppression of synaptic engulfment can repair cognitive deficits points to an essential opportunity for intervention that can prevent the loss of intact synapses. In this study, we focus on the latest research on the role and mechanisms of complement-mediated microglial synaptic pruning at different stages of AD to find the right targets that could interfere with complement dysregulation and be relevant for therapeutic intervention at the early stages of the disease.
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Affiliation(s)
- Gunel Ayyubova
- Department of Cytology, Embryology and Histology, Azerbaijan Medical University, Baku 370022, Azerbaijan;
| | - Nadeem Fazal
- College of Health Sciences and Pharmacy, Chicago State University, Chicago, IL 60628, USA
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Khoshneviszadeh M, Henneicke S, Pirici D, Senthilnathan A, Morton L, Arndt P, Kaushik R, Norman O, Jukkola J, Dunay IR, Seidenbecher C, Heikkinen A, Schreiber S, Dityatev A. Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease. Matrix Biol 2024; 128:39-64. [PMID: 38387749 DOI: 10.1016/j.matbio.2024.02.007] [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: 04/26/2023] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1-/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old Col18a1-/- mice. None of the Col18a1-/- mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. Col18a1 deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.
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Affiliation(s)
- Mahsima Khoshneviszadeh
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany
| | - Solveig Henneicke
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany
| | - Daniel Pirici
- Department of Histology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | | | - Lorena Morton
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
| | - Philipp Arndt
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany
| | - Rahul Kaushik
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
| | - Oula Norman
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
| | - Jari Jukkola
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
| | - Ildiko Rita Dunay
- Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany; Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany
| | - Constanze Seidenbecher
- Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany; Leibniz Institute for Neurobiology, Magdeburg, Germany; Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany
| | - Anne Heikkinen
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland
| | - Stefanie Schreiber
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany; Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany.
| | - Alexander Dityatev
- German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany; Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
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14
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Elghiriani MA, Naga SS, Hameed IA, Elgohary IE, Mansour AR. The role of online hemodiafiltration with endogenous reinfusion in the treatment of systemic lupus erythematosus activity resistant to conventional therapy. FRONTIERS IN NEPHROLOGY 2024; 4:1269852. [PMID: 38586116 PMCID: PMC10995452 DOI: 10.3389/fneph.2024.1269852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 02/05/2024] [Indexed: 04/09/2024]
Abstract
Introduction Lupus is a diverse autoimmune disease with autoantibody formation. Lupus nephritis carries a grave prognosis. Complement involvement, namely, C1q deficiency, is linked to activity and renal involvement and could help in their assessment. LN therapies include plasma exchange, immune adsorption, and probably hemodiafiltration with online endogenous reinfusion (HFR), together with traditional immunosuppressive therapies. Aim The aim of this study was to evaluate the role of HFR in improving signs and symptoms of systemic lupus erythematosus (SLE) activity and laboratory parameters in cases not responding to traditional immunosuppressive therapy. Settings and design A controlled clinical study was conducted on 60 patients with lupus from Group A that was subdivided into two groups: cases 1 (47 patients), those who received traditional medical treatment, and cases 2 (13 patients), those who underwent HFR in addition to medical treatment. Group B consisted of two subgroups: control 1, composed of 20 healthy age- and sex-matched volunteers, and control 2, consisting of 10 cases with different glomerular diseases other than lupus. Methods and materials Serum C1q was determined before and after the HFR as well as induction by medical treatment. Disease activity was assessed using SLEDAI-2K with a responder index of 50; quality of life was assessed using SLEQOL v2, and HFR was performed for the non-responder group. Results C1q was lower in cases. It can efficiently differentiate between SLE patients and healthy controls with a sensitivity of 81.67% and a specificity of 90%. It can also efficiently differentiate between SLE patients and the control 2 group (non-lupus patients with renal glomerular disease) with a sensitivity of 83.33% and a specificity of 100%. C1q was more consumed in proliferative lupus, and correlated with anti-ds DNA, C3, and C4. Conclusions C1q efficiently discriminates lupus patients and correlates with proliferative forms. HFR might ameliorate lupus activity and restore C1q.
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Affiliation(s)
- Mohammed A. Elghiriani
- Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Salah S. Naga
- Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Ibtessam A. Hameed
- Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Iman E. Elgohary
- Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Amal R. Mansour
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Gomez‐Arboledas A, Fonseca MI, Kramar E, Chu S, Schartz ND, Selvan P, Wood MA, Tenner AJ. C5aR1 signaling promotes region- and age-dependent synaptic pruning in models of Alzheimer's disease. Alzheimers Dement 2024; 20:2173-2190. [PMID: 38278523 PMCID: PMC10984438 DOI: 10.1002/alz.13682] [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: 10/02/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 01/28/2024]
Abstract
INTRODUCTION Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD. METHODS A combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD. RESULTS Genetic ablation or pharmacological inhibition of C5aR1 partially rescues excessive pre-synaptic pruning and synaptic loss in an age and region-dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP). DISCUSSION Reduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD. HIGHLIGHTS C5aR1 ablation restores long-term potentiation in the Arctic model of AD. C5aR1 ablation rescues region specific excessive pre-synaptic loss. C5aR1 antagonist, PMX205, rescues VGlut1 loss in the Tg2576 model of AD. C1q tagging is not sufficient to induce VGlut1 microglial ingestion. Astrocytes contribute to excessive pre-synaptic loss at late stages of the disease.
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Affiliation(s)
- Angela Gomez‐Arboledas
- Department of Molecular Biology and BiochemistryUniversity of CaliforniaIrvineCaliforniaUSA
| | - Maria I. Fonseca
- Department of Molecular Biology and BiochemistryUniversity of CaliforniaIrvineCaliforniaUSA
| | - Enikö Kramar
- Department of Neurobiology and BehaviorUniversity of CaliforniaIrvineCaliforniaUSA
| | - Shu‐Hui Chu
- Department of Molecular Biology and BiochemistryUniversity of CaliforniaIrvineCaliforniaUSA
| | - Nicole D. Schartz
- Department of Molecular Biology and BiochemistryUniversity of CaliforniaIrvineCaliforniaUSA
| | - Purnika Selvan
- Department of Molecular Biology and BiochemistryUniversity of CaliforniaIrvineCaliforniaUSA
| | - Marcelo A. Wood
- Department of Neurobiology and BehaviorUniversity of CaliforniaIrvineCaliforniaUSA
| | - Andrea J. Tenner
- Department of Molecular Biology and BiochemistryUniversity of CaliforniaIrvineCaliforniaUSA
- Department of Neurobiology and BehaviorUniversity of CaliforniaIrvineCaliforniaUSA
- Department of Pathology and Laboratory MedicineUniversity of CaliforniaSchool of MedicineIrvineCaliforniaUSA
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16
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Djurišić M. Immune receptors and aging brain. Biosci Rep 2024; 44:BSR20222267. [PMID: 38299364 PMCID: PMC10866841 DOI: 10.1042/bsr20222267] [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: 07/20/2023] [Revised: 01/08/2024] [Accepted: 01/29/2024] [Indexed: 02/02/2024] Open
Abstract
Aging brings about a myriad of degenerative processes throughout the body. A decrease in cognitive abilities is one of the hallmark phenotypes of aging, underpinned by neuroinflammation and neurodegeneration occurring in the brain. This review focuses on the role of different immune receptors expressed in cells of the central and peripheral nervous systems. We will discuss how immune receptors in the brain act as sentinels and effectors of the age-dependent shift in ligand composition. Within this 'old-age-ligand soup,' some immune receptors contribute directly to excessive synaptic weakening from within the neuronal compartment, while others amplify the damaging inflammatory environment in the brain. Ultimately, chronic inflammation sets up a positive feedback loop that increases the impact of immune ligand-receptor interactions in the brain, leading to permanent synaptic and neuronal loss.
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Affiliation(s)
- Maja Djurišić
- Departments of Biology, Neurobiology, and Bio-X, Stanford University, Stanford, CA 94305, U.S.A
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17
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Rinauro DJ, Chiti F, Vendruscolo M, Limbocker R. Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases. Mol Neurodegener 2024; 19:20. [PMID: 38378578 PMCID: PMC10877934 DOI: 10.1186/s13024-023-00651-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 08/17/2023] [Indexed: 02/22/2024] Open
Abstract
The conversion of native peptides and proteins into amyloid aggregates is a hallmark of over 50 human disorders, including Alzheimer's and Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the amyloid formation process as the primary cytotoxic agents in many of these devastating conditions. In this review, we analyze the processes by which oligomers are formed, their structures, physicochemical properties, population dynamics, and the mechanisms of their cytotoxicity. We then focus on drug discovery strategies that target the formation of oligomers and their ability to disrupt cell physiology and trigger degenerative processes.
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Affiliation(s)
- Dillon J Rinauro
- Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK
| | - Fabrizio Chiti
- Section of Biochemistry, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy
| | - Michele Vendruscolo
- Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
| | - Ryan Limbocker
- Department of Chemistry and Life Science, United States Military Academy, West Point, NY, 10996, USA.
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18
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Batista AF, Khan KA, Papavergi MT, Lemere CA. The Importance of Complement-Mediated Immune Signaling in Alzheimer's Disease Pathogenesis. Int J Mol Sci 2024; 25:817. [PMID: 38255891 PMCID: PMC10815224 DOI: 10.3390/ijms25020817] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/24/2024] Open
Abstract
As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer's disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.
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Affiliation(s)
- André F. Batista
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (A.F.B.); (K.A.K.); (M.-T.P.)
| | - Khyrul A. Khan
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (A.F.B.); (K.A.K.); (M.-T.P.)
| | - Maria-Tzousi Papavergi
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (A.F.B.); (K.A.K.); (M.-T.P.)
- School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Cynthia A. Lemere
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (A.F.B.); (K.A.K.); (M.-T.P.)
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19
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Thakur K, Khan H, Grewal AK, Singh TG. Nuclear orphan receptors: A novel therapeutic agent in neuroinflammation. Int Immunopharmacol 2023; 124:110845. [PMID: 37690241 DOI: 10.1016/j.intimp.2023.110845] [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: 03/07/2023] [Revised: 08/14/2023] [Accepted: 08/20/2023] [Indexed: 09/12/2023]
Abstract
Orphan receptors constitute a historically varied subsection of a superfamily of nuclear receptors. Nuclear receptors regulate gene expression in response to ligand signals and are particularly alluring therapeutic targets for chronic illnesses. Neuroinflammation and neurodegenerative diseases have been linked to these orphan nuclear receptors. Preclinical and clinical evidence suggests that orphan receptors could serve as future targets in neuroinflammation, such as Parkinson's disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), and Cerebral Ischemia. Given the therapeutic relevance of certain orphan receptors in a variety of disorders, their potential in neuroinflammation remains unproven. There is substantial evidence that ligand-activated transcription factors have great promise for preventing neurodegenerative and neurological disorders, with certain orphan nuclear receptors i.e., PPARγ, NR4As, and orphan GPCRs holding particularly high potential. Based on previous findings, we attempted to determine the contribution of PPAR, NR4As, and orphan GPCRs-regulated neuroinflammation to the pathogenesis of these disorders and their potential to become novel therapeutic targets.
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Affiliation(s)
- Kiran Thakur
- Chitkara College of Pharmacy, Chitkara University, 140401 Punjab, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, 140401 Punjab, India
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20
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Lee Y, Yeo IS, Kim N, Lee DK, Kim KT, Yoon J, Yi J, Hong YB, Choi BO, Kosodo Y, Kim D, Park J, Song MR. Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2. eLife 2023; 12:e84596. [PMID: 37869988 PMCID: PMC10637776 DOI: 10.7554/elife.84596] [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: 10/31/2022] [Accepted: 10/11/2023] [Indexed: 10/24/2023] Open
Abstract
The fidelity of motor control requires the precise positional arrangement of motor pools and the establishment of synaptic connections between them. During neural development in the spinal cord, motor nerves project to specific target muscles and receive proprioceptive input from these muscles via the sensorimotor circuit. LIM-homeodomain transcription factors are known to play a crucial role in successively restricting specific motor neuronal fates. However, their exact contribution to limb-based motor pools and locomotor circuits has not been fully understood. To address this, we conducted an investigation into the role of Isl2, a LIM-homeodomain transcription factor, in motor pool organization. We found that deletion of Isl2 led to the dispersion of motor pools, primarily affecting the median motor column (MMC) and lateral motor column (LMC) populations. Additionally, hindlimb motor pools lacked Etv4 expression, and we observed reduced terminal axon branching and disorganized neuromuscular junctions in Isl2-deficient mice. Furthermore, we performed transcriptomic analysis on the spinal cords of Isl2-deficient mice and identified a variety of downregulated genes associated with motor neuron (MN) differentiation, axon development, and synapse organization in hindlimb motor pools. As a consequence of these disruptions, sensorimotor connectivity and hindlimb locomotion were impaired in Isl2-deficient mice. Taken together, our findings highlight the critical role of Isl2 in organizing motor pool position and sensorimotor circuits in hindlimb motor pools. This research provides valuable insights into the molecular mechanisms governing motor control and its potential implications for understanding motor-related disorders in humans.
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Affiliation(s)
- Yunjeong Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-guGwangjuRepublic of Korea
| | - In Seo Yeo
- School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-guGwangjuRepublic of Korea
| | - Namhee Kim
- Fermentation Regulation Technology Research Group, World Institute of KimchiGwangjuRepublic of Korea
| | - Dong-Keun Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-guGwangjuRepublic of Korea
| | - Kyung-Tai Kim
- Jeonbuk Department of Inhalation Research, Korea Institute of ToxicologyJeongeup-siRepublic of Korea
| | - Jiyoung Yoon
- School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-guGwangjuRepublic of Korea
| | - Jawoon Yi
- School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-guGwangjuRepublic of Korea
| | - Young Bin Hong
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoulRepublic of Korea
- Department of Biochemistry, College of Medicine, Dong-A UniversityBusanRepublic of Korea
| | - Byung-Ok Choi
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoulRepublic of Korea
| | - Yoichi Kosodo
- Korea Brain Research InstituteDaeguRepublic of Korea
| | - Daesoo Kim
- Department of Brain and Cognitive Sciences, Korea Advanced Institute of Science and Technology (KAIST)DaejeonRepublic of Korea
| | - Jihwan Park
- School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-guGwangjuRepublic of Korea
| | - Mi-Ryoung Song
- School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-guGwangjuRepublic of Korea
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21
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Gomez-Arboledas A, Fonseca MI, Kramar E, Chu SH, Schartz N, Selvan P, Wood MA, Tenner AJ. C5aR1 signaling promotes region and age dependent synaptic pruning in models of Alzheimer's Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.29.560234. [PMID: 37873302 PMCID: PMC10592845 DOI: 10.1101/2023.09.29.560234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
INTRODUCTION Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD. METHODS A combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD. RESULTS Genetic ablation or pharmacological inhibition of C5aR1 rescues the excessive pre-synaptic pruning and synaptic loss in an age and region dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP). DISCUSSION Reduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.
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Affiliation(s)
- Angela Gomez-Arboledas
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Maria I. Fonseca
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Enikö Kramar
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA
| | - Shu-Hui Chu
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Nicole Schartz
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Purnika Selvan
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Marcelo A. Wood
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA
| | - Andrea J. Tenner
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA
- Department of Pathology and Laboratory Medicine, University of California, Irvine, School of Medicine, Irvine, CA 92697, USA
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22
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Xing Y, Zhang D, Fang L, Wang J, Liu C, Wu D, Liu X, Wang X, Min W. Complement in Human Brain Health: Potential of Dietary Food in Relation to Neurodegenerative Diseases. Foods 2023; 12:3580. [PMID: 37835232 PMCID: PMC10572247 DOI: 10.3390/foods12193580] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
The complement pathway is a major component of the innate immune system, which is critical for recognizing and clearing pathogens that rapidly react to defend the body against external pathogens. Many components of this pathway are expressed throughout the brain and play a beneficial role in synaptic pruning in the developing central nervous system (CNS). However, excessive complement-mediated synaptic pruning in the aging or injured brain may play a contributing role in a wide range of neurodegenerative diseases. Complement Component 1q (C1q), an initiating recognition molecule of the classical complement pathway, can interact with a variety of ligands and perform a range of functions in physiological and pathophysiological conditions of the CNS. This review considers the function and immunomodulatory mechanisms of C1q; the emerging role of C1q on synaptic pruning in developing, aging, or pathological CNS; the relevance of C1q; the complement pathway to neurodegenerative diseases; and, finally, it summarizes the foods with beneficial effects in neurodegenerative diseases via C1q and complement pathway and highlights the need for further research to clarify these roles. This paper aims to provide references for the subsequent study of food functions related to C1q, complement, neurodegenerative diseases, and human health.
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Affiliation(s)
- Yihang Xing
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China; (Y.X.); (D.Z.); (L.F.); (J.W.); (C.L.); (D.W.); (X.L.)
| | - Dingwen Zhang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China; (Y.X.); (D.Z.); (L.F.); (J.W.); (C.L.); (D.W.); (X.L.)
| | - Li Fang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China; (Y.X.); (D.Z.); (L.F.); (J.W.); (C.L.); (D.W.); (X.L.)
| | - Ji Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China; (Y.X.); (D.Z.); (L.F.); (J.W.); (C.L.); (D.W.); (X.L.)
| | - Chunlei Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China; (Y.X.); (D.Z.); (L.F.); (J.W.); (C.L.); (D.W.); (X.L.)
| | - Dan Wu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China; (Y.X.); (D.Z.); (L.F.); (J.W.); (C.L.); (D.W.); (X.L.)
| | - Xiaoting Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China; (Y.X.); (D.Z.); (L.F.); (J.W.); (C.L.); (D.W.); (X.L.)
| | - Xiyan Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China; (Y.X.); (D.Z.); (L.F.); (J.W.); (C.L.); (D.W.); (X.L.)
| | - Weihong Min
- College of Food and Health, Zhejiang A&F University, Hangzhou 311300, China
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23
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Zhou Y, Bhatt H, Mojica CA, Xin H, Pessina MA, Rosene DL, Moore TL, Medalla M. Mesenchymal-derived extracellular vesicles enhance microglia-mediated synapse remodeling after cortical injury in aging Rhesus monkeys. J Neuroinflammation 2023; 20:201. [PMID: 37660145 PMCID: PMC10475204 DOI: 10.1186/s12974-023-02880-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 08/23/2023] [Indexed: 09/04/2023] Open
Abstract
Understanding the microglial neuro-immune interactions in the primate brain is vital to developing therapeutics for cortical injury, such as stroke or traumatic brain injury. Our previous work showed that mesenchymal-derived extracellular vesicles (MSC-EVs) enhanced motor recovery in aged rhesus monkeys following injury of primary motor cortex (M1), by promoting homeostatic ramified microglia, reducing injury-related neuronal hyperexcitability, and enhancing synaptic plasticity in perilesional cortices. A focal lesion was induced via surgical ablation of pial blood vessels over lying the cortical hand representation of M1 of aged female rhesus monkeys, that received intravenous infusions of either vehicle (veh) or EVs 24 h and again 14 days post-injury. The current study used this same cohort to address how these injury- and recovery-associated changes relate to structural and molecular interactions between microglia and neuronal synapses. Using multi-labeling immunohistochemistry, high-resolution microscopy, and gene expression analysis, we quantified co-expression of synaptic markers (VGLUTs, GLURs, VGAT, GABARs), microglia markers (Iba1, P2RY12), and C1q, a complement pathway protein for microglia-mediated synapse phagocytosis, in perilesional M1 and premotor cortices (PMC). We compared this lesion cohort to age-matched non-lesion controls (ctr). Our findings revealed a lesion-related loss of excitatory synapses in perilesional areas, which was ameliorated by EV treatment. Further, we found region-dependent effects of EVs on microglia and C1q expression. In perilesional M1, EV treatment and enhanced functional recovery were associated with increased expression of C1q + hypertrophic microglia, which are thought to have a role in debris-clearance and anti-inflammatory functions. In PMC, EV treatment was associated with decreased C1q + synaptic tagging and microglia-spine contacts. Our results suggest that EV treatment may enhance synaptic plasticity via clearance of acute damage in perilesional M1, and thereby preventing chronic inflammation and excessive synaptic loss in PMC. These mechanisms may act to preserve synaptic cortical motor networks and a balanced normative M1/PMC synaptic function to support functional recovery after injury.
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Affiliation(s)
- Yuxin Zhou
- Department of Anatomy & Neurobiology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA
| | - Hrishti Bhatt
- Department of Anatomy & Neurobiology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA
| | - Chromewell A Mojica
- Department of Anatomy & Neurobiology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA
| | - Hongqi Xin
- Department of Neurology, Henry Ford Health Systems, Detroit, MI, 48202, USA
| | - Monica A Pessina
- Department of Anatomy & Neurobiology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA
| | - Douglas L Rosene
- Department of Anatomy & Neurobiology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA
- Center for Systems Neuroscience, Boston University, Boston, MA, 02215, USA
| | - Tara L Moore
- Department of Anatomy & Neurobiology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA
- Center for Systems Neuroscience, Boston University, Boston, MA, 02215, USA
| | - Maria Medalla
- Department of Anatomy & Neurobiology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA.
- Center for Systems Neuroscience, Boston University, Boston, MA, 02215, USA.
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24
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Guan PP, Ge TQ, Wang P. As a Potential Therapeutic Target, C1q Induces Synapse Loss Via Inflammasome-activating Apoptotic and Mitochondria Impairment Mechanisms in Alzheimer's Disease. J Neuroimmune Pharmacol 2023; 18:267-284. [PMID: 37386257 DOI: 10.1007/s11481-023-10076-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 06/16/2023] [Indexed: 07/01/2023]
Abstract
C1q, the initiator of the classical pathway of the complement system, is activated during Alzheimer's disease (AD) development and progression and is especially associated with the production and deposition of β-amyloid protein (Aβ) and phosphorylated tau in β-amyloid plaques (APs) and neurofibrillary tangles (NFTs). Activation of C1q is responsible for induction of synapse loss, leading to neurodegeneration in AD. Mechanistically, C1q could activate glial cells, which results in the loss of synapses via regulation of synapse pruning and phagocytosis in AD. In addition, C1q induces neuroinflammation by inducing proinflammatory cytokine secretion, which is partially mediated by inflammasome activation. Activation of inflammasomes might mediate the effects of C1q on induction of synapse apoptosis. On the other hand, activation of C1q impairs mitochondria, which hinders the renovation and regeneration of synapses. All these actions of C1q contribute to the loss of synapses during neurodegeneration in AD. Therefore, pharmacological, or genetic interventions targeting C1q may provide potential therapeutic strategies for combating AD.
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Affiliation(s)
- Pei-Pei Guan
- College of Life and Health Sciences, Northeastern University, 110819, Shenyang, People's Republic of China
| | - Tong-Qi Ge
- College of Life and Health Sciences, Northeastern University, 110819, Shenyang, People's Republic of China
| | - Pu Wang
- College of Life and Health Sciences, Northeastern University, 110819, Shenyang, People's Republic of China.
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25
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Cheng Y, Chen T, Hu J. Genetic analysis of potential biomarkers and therapeutic targets in neuroinflammation from sporadic Creutzfeldt-Jakob disease. Sci Rep 2023; 13:14122. [PMID: 37644077 PMCID: PMC10465546 DOI: 10.1038/s41598-023-41066-9] [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: 05/26/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023] Open
Abstract
This study aimed to identify hub genes and pathological mechanisms related to neuroinflammation in Sporadic Creutzfeldt-Jakob disease (SCJD) based on comprehensive bioinformatics. SCJD and normal samples were collected from GSE160208. Weighted gene co-expression network analysis (WGCNA) and Limma R package were used to obtain key genes, which were used for enrichment and immune cell infiltration analyses. Protein-protein interaction (PPI) network, cytoHubba, and machine learning were used to screen the central genes of SCJD. The chemicals related to hub genes were predicted and explored by molecular docking. 88 candidate genes were screened. Enrichment analysis showed they were mainly related to bacterial and viral infection and immune cell activation. Immune cell infiltration analysis suggested that immune cell activation and altered activity of the immune system are involved in the progression of SCJD. After identifying hub genes, KIT and SPP1 had higher diagnostic efficacy for SCJD (AUC > 0.9), so they were identified as central genes. The molecular docking results showed hub genes both docked well with Tretinoin. KIT, SPP1, and Tretinoin are essential in developing neuroinflammation in SCJD and may provide new ideas for diagnosing and treating SCJD.
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Affiliation(s)
- Yajing Cheng
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Ting Chen
- Department of Neurology, Shenzhen Second People's Hospital, Shenzhen, China
| | - Jun Hu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China.
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26
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Schartz ND, Liang HY, Carvalho K, Chu SH, Mendoza-Arvilla A, Petrisko TJ, Gomez-Arboledas A, Mortazavi A, Tenner AJ. C5aR1 antagonism suppresses inflammatory glial gene expression and alters cellular signaling in an aggressive Alzheimer's model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.22.554306. [PMID: 37662399 PMCID: PMC10473603 DOI: 10.1101/2023.08.22.554306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. Pharmacologic inhibition of C5aR1 reduces plaque load, gliosis and memory deficits in animal models. However, the cellular basis underlying this neuroprotection and which processes were the consequence of amyloid reduction vs alteration of the response to amyloid were unclear. In the Arctic model, the C5aR1 antagonist PMX205 did not reduce plaque load, but deficits in short-term memory in female mice were prevented. Hippocampal single cell and single nucleus RNA-seq clusters revealed C5aR1 dependent and independent gene expression and cell-cell communication. Microglial clusters containing neurotoxic disease-associated microglial genes were robustly upregulated in Arctic mice and drastically reduced with PMX205 treatment, while genes in microglia clusters that were overrepresented in the Arctic-PMX205 vs Arctic group were associated with synapse organization and transmission and learning. PMX205 treatment also reduced some A-1 astrocyte genes. In spite of changes in transcript levels, overall protein levels of some reactive glial markers were relatively unchanged by C5aR1 antagonism, as were clusters associated with protective responses to injury. C5aR1 inhibition promoted signaling pathways associated with cell growth and repair, such as TGFβ and FGF, in Arctic mice, while suppressing inflammatory pathways including PROS, Pecam1, and EPHA. In conclusion, pharmacologic C5aR1 inhibition prevents cognitive loss, limits microglial polarization to a detrimental inflammatory state and permits neuroprotective responses, as well as leaving protective functions of complement intact, making C5aR1 antagonism an attractive therapeutic strategy for individuals with AD.
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Affiliation(s)
- Nicole D. Schartz
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA 92697
| | - Heidi Y. Liang
- Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA 92697
| | - Klebea Carvalho
- Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA 92697
| | - Shu-Hui Chu
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA 92697
| | - Adrian Mendoza-Arvilla
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA 92697
| | - Tiffany J. Petrisko
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA 92697
| | - Angela Gomez-Arboledas
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA 92697
| | - Ali Mortazavi
- Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA 92697
| | - Andrea J. Tenner
- Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA 92697
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697
- Department of Pathology and Laboratory Medicine, University of California, Irvine, School of Medicine, Irvine, CA 92697
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27
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Rochín-Hernández LJ, Jiménez-Acosta MA, Ramírez-Reyes L, Figueroa-Corona MDP, Sánchez-González VJ, Orozco-Barajas M, Meraz-Ríos MA. The Proteome Profile of Olfactory Ecto-Mesenchymal Stem Cells-Derived from Patients with Familial Alzheimer's Disease Reveals New Insights for AD Study. Int J Mol Sci 2023; 24:12606. [PMID: 37628788 PMCID: PMC10454072 DOI: 10.3390/ijms241612606] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
Alzheimer's disease (AD), the most common neurodegenerative disease and the first cause of dementia worldwide, has no effective treatment, and its pathological mechanisms are not yet fully understood. We conducted this study to explore the proteomic differences associated with Familial Alzheimer's Disease (FAD) in olfactory ecto-mesenchymal stem cells (MSCs) derived from PSEN1 (A431E) mutation carriers compared with healthy donors paired by age and gender through two label-free liquid chromatography-mass spectrometry approaches. The first analysis compared carrier 1 (patient with symptoms, P1) and its control (healthy donor, C1), and the second compared carrier 2 (patient with pre-symptoms, P2) with its respective control cells (C2) to evaluate whether the protein alterations presented in the symptomatic carrier were also present in the pre-symptom stages. Finally, we analyzed the differentially expressed proteins (DEPs) for biological and functional enrichment. These proteins showed impaired expression in a stage-dependent manner and are involved in energy metabolism, vesicle transport, actin cytoskeleton, cell proliferation, and proteostasis pathways, in line with previous AD reports. Our study is the first to conduct a proteomic analysis of MSCs from the Jalisco FAD patients in two stages of the disease (symptomatic and presymptomatic), showing these cells as a new and excellent in vitro model for future AD studies.
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Affiliation(s)
- Lory J. Rochín-Hernández
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Instituto Politécnico Nacional 2508, Ciudad de México 07360, Mexico; (L.J.R.-H.); (M.A.J.-A.); (M.d.P.F.-C.)
| | - Miguel A. Jiménez-Acosta
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Instituto Politécnico Nacional 2508, Ciudad de México 07360, Mexico; (L.J.R.-H.); (M.A.J.-A.); (M.d.P.F.-C.)
| | - Lorena Ramírez-Reyes
- Unidad de Genómica, Proteómica y Metabolómica, Laboratorio Nacional de Servicios Experimentales (LaNSE), Centro de Investigación y de Estudios Avanzados, Ciudad de México 07360, Mexico;
| | - María del Pilar Figueroa-Corona
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Instituto Politécnico Nacional 2508, Ciudad de México 07360, Mexico; (L.J.R.-H.); (M.A.J.-A.); (M.d.P.F.-C.)
| | - Víctor J. Sánchez-González
- Centro Universitario de Los Altos, Universidad de Guadalajara, Tepatitlán de Morelos 47620, Mexico; (V.J.S.-G.); (M.O.-B.)
| | - Maribel Orozco-Barajas
- Centro Universitario de Los Altos, Universidad de Guadalajara, Tepatitlán de Morelos 47620, Mexico; (V.J.S.-G.); (M.O.-B.)
| | - Marco A. Meraz-Ríos
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Instituto Politécnico Nacional 2508, Ciudad de México 07360, Mexico; (L.J.R.-H.); (M.A.J.-A.); (M.d.P.F.-C.)
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28
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Yang MH, Ho TC, Chang CC, Su YS, Yuan CH, Chuang KP, Tyan YC. Utilizing Proteomic Approaches to Uncover the Neuroprotective Effects of ACE Inhibitors: Implications for Alzheimer's Disease Treatment. Molecules 2023; 28:5938. [PMID: 37630190 PMCID: PMC10459293 DOI: 10.3390/molecules28165938] [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: 05/12/2023] [Revised: 06/30/2023] [Accepted: 07/18/2023] [Indexed: 08/27/2023] Open
Abstract
Two types of angiotensin-converting enzyme (ACE) inhibitors, lisinopril and benazepril HCl, were tested in neuroblastoma cells and found to upregulate low-density lipoprotein-receptor-related protein 1B (LRP1B) and 14-3-3 protein zeta/delta. Additionally, benazepril HCl was found to increase the expression of calreticulin. The upregulation of these proteins by ACE inhibitors may contribute to the amelioration of cognitive deficits in Alzheimer's disease/dementia, as well as the clinically observed deceleration of functional decline in Alzheimer's patients. This discovery suggests that the supplementation of ACE inhibitors may promote neuronal cell survival independently of their antihypertensive effect. Overall, these findings indicate that ACE inhibitors may be a promising avenue for developing effective treatments for Alzheimer's disease.
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Affiliation(s)
- Ming-Hui Yang
- Division of General & Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Tzu-Chuan Ho
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chin-Chuan Chang
- Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yuh-Shan Su
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Cheng-Hui Yuan
- Mass Spectrometry Laboratory, Department of Chemistry, National University of Singapore, Singapore 119077, Singapore
| | - Kuo-Pin Chuang
- School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- International Degree Program in Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Companion Animal Research Center, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Yu-Chang Tyan
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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29
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Zhou Y, Bhatt H, Mojica CA, Xin H, Pessina M, Rosene DL, Moore TL, Medalla M. Mesenchymal-Derived Extracellular Vesicles Enhance Microglia-mediated Synapse Remodeling after Cortical Injury in Rhesus Monkeys. RESEARCH SQUARE 2023:rs.3.rs-2917340. [PMID: 37292805 PMCID: PMC10246272 DOI: 10.21203/rs.3.rs-2917340/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Understanding the microglial neuro-immune interactions in the primate brain is vital to developing therapeutics for cortical injury, such as stroke. Our previous work showed that mesenchymal-derived extracellular vesicles (MSC-EVs) enhanced motor recovery in aged rhesus monkeys post-injury of primary motor cortex (M1), by promoting homeostatic ramified microglia, reducing injury-related neuronal hyperexcitability, and enhancing synaptic plasticity in perilesional cortices. The current study addresses how these injury- and recovery-associated changes relate to structural and molecular interactions between microglia and neuronal synapses. Using multi-labeling immunohistochemistry, high resolution microscopy, and gene expression analysis, we quantified co-expression of synaptic markers (VGLUTs, GLURs, VGAT, GABARs), microglia markers (Iba-1, P2RY12), and C1q, a complement pathway protein for microglia-mediated synapse phagocytosis, in perilesional M1 and premotor cortices (PMC) of monkeys with intravenous infusions of either vehicle (veh) or EVs post-injury. We compared this lesion cohort to aged-matched non-lesion controls. Our findings revealed a lesion-related loss of excitatory synapses in perilesional areas, which was ameliorated by EV treatment. Further, we found region-dependent effects of EV on microglia and C1q expression. In perilesional M1, EV treatment and enhanced functional recovery were associated with increased expression of C1q + hypertrophic microglia, which are thought to have a role in debris-clearance and anti-inflammatory functions. In PMC, EV treatment was associated with decreased C1q + synaptic tagging and microglial-spine contacts. Our results provided evidence that EV treatment facilitated synaptic plasticity by enhancing clearance of acute damage in perilesional M1, and thereby preventing chronic inflammation and excessive synaptic loss in PMC. These mechanisms may act to preserve synaptic cortical motor networks and a balanced normative M1/PMC synaptic connectivity to support functional recovery after injury.
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Affiliation(s)
- Yuxin Zhou
- Boston University Chobanian & Avedisian School of Medicine
| | - Hrishti Bhatt
- Boston University Chobanian & Avedisian School of Medicine
| | | | | | - Monica Pessina
- Boston University Chobanian & Avedisian School of Medicine
| | | | - Tara L Moore
- Boston University Chobanian & Avedisian School of Medicine
| | - Maria Medalla
- Boston University Chobanian & Avedisian School of Medicine
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30
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Grover L, Sklioutovskaya-Lopez K, Parkman JK, Wang K, Hendricks E, Adams-Duffield J, Kim JH. Diet, sex, and genetic predisposition to obesity and type 2 diabetes modulate motor and anxiety-related behaviors in mice, and alter cerebellar gene expression. Behav Brain Res 2023; 445:114376. [PMID: 36868363 PMCID: PMC10065959 DOI: 10.1016/j.bbr.2023.114376] [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: 08/15/2022] [Revised: 12/28/2022] [Accepted: 02/28/2023] [Indexed: 03/05/2023]
Abstract
Obesity and type 2 diabetes (T2D) are serious health problems linked to neurobehavioral alterations. We compared motor function, anxiety-related behavior, and cerebellar gene expression in TALLYHO/Jng (TH), a polygenic model prone to insulin resistance, obesity, and T2D, and normal C57BL/6 J (B6) mice. Male and female mice were weaned onto chow or high fat (HF) diet at 4 weeks of age (wk), and experiments conducted at young (5 wk) and old (14 - 20 wk) ages. In the open field, distance traveled was significantly lower in TH (vs. B6). For old mice, anxiety-like behavior (time in edge zone) was significantly increased for TH (vs B6), females (vs males), and for both ages HF diet (vs chow). In Rota-Rod testing, latency to fall was significantly shorter in TH (vs B6). For young mice, longer latencies to fall were observed for females (vs males) and HF (vs chow). Grip strength in young mice was greater in TH (vs B6), and there was a diet-strain interaction, with TH on HF showing increased strength, whereas B6 on HF showed decreased strength. For older mice, there was a strain-sex interaction, with B6 males (but not TH males) showing increased strength compared to the same strain females. There were significant sex differences in cerebellar mRNA levels, with Tnfα higher, and Glut4 and Irs2 lower in females (vs males). There were significant strain effects for Gfap and Igf1 mRNA levels with lower in TH (vs B6). Altered cerebellar gene expression may contribute to strain differences in coordination and locomotion.
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Affiliation(s)
- Lawrence Grover
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | | | - Jacaline K Parkman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Katherine Wang
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Emily Hendricks
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Jessica Adams-Duffield
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Jung Han Kim
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
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31
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Bohlson SS, Tenner AJ. Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation. Annu Rev Immunol 2023; 41:431-452. [PMID: 36750318 DOI: 10.1146/annurev-immunol-101921-035639] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
The complement system is an ancient collection of proteolytic cascades with well-described roles in regulation of innate and adaptive immunity. With the convergence of a revolution in complement-directed clinical therapeutics, the discovery of specific complement-associated targetable pathways in the central nervous system, and the development of integrated multi-omic technologies that have all emerged over the last 15 years, precision therapeutic targeting in Alzheimer disease and other neurodegenerative diseases and processes appears to be within reach. As a sensor of tissue distress, the complement system protects the brain from microbial challenge as well as the accumulation of dead and/or damaged molecules and cells. Additional more recently discovered diverse functions of complement make it of paramount importance to design complement-directed neurotherapeutics such that the beneficial roles in neurodevelopment, adult neural plasticity, and neuroprotective functions of the complement system are retained.
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Affiliation(s)
- Suzanne S Bohlson
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California, USA; ,
| | - Andrea J Tenner
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California, USA; ,
- Department of Neurobiology and Behavior, University of California, Irvine, California, USA
- Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Irvine, California, USA
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32
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Castillo-Arellano J, Canseco-Alba A, Cutler SJ, León F. The Polypharmacological Effects of Cannabidiol. Molecules 2023; 28:3271. [PMID: 37050032 PMCID: PMC10096752 DOI: 10.3390/molecules28073271] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/23/2023] [Accepted: 03/30/2023] [Indexed: 04/09/2023] Open
Abstract
Cannabidiol (CBD) is a major phytocannabinoid present in Cannabis sativa (Linneo, 1753). This naturally occurring secondary metabolite does not induce intoxication or exhibit the characteristic profile of drugs of abuse from cannabis like Δ9-tetrahydrocannabinol (∆9-THC) does. In contrast to ∆9-THC, our knowledge of the neuro-molecular mechanisms of CBD is limited, and its pharmacology, which appears to be complex, has not yet been fully elucidated. The study of the pharmacological effects of CBD has grown exponentially in recent years, making it necessary to generate frequently updated reports on this important metabolite. In this article, a rationalized integration of the mechanisms of action of CBD on molecular targets and pharmacological implications in animal models and human diseases, such as epilepsy, pain, neuropsychiatric disorders, Alzheimer's disease, and inflammatory diseases, are presented. We identify around 56 different molecular targets for CBD, including enzymes and ion channels/metabotropic receptors involved in neurologic conditions. Herein, we compiled the knowledge found in the scientific literature on the multiple mechanisms of actions of CBD. The in vitro and in vivo findings are essential for fully understanding the polypharmacological nature of this natural product.
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Affiliation(s)
- Jorge Castillo-Arellano
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Ana Canseco-Alba
- Laboratory of Reticular Formation Physiology, National Institute of Neurology and Neurosurgery of Mexico (INNN), Mexico City 14269, Mexico
| | - Stephen J. Cutler
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Francisco León
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
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Zhang W, Chen Y, Pei H. C1q and central nervous system disorders. Front Immunol 2023; 14:1145649. [PMID: 37033981 PMCID: PMC10076750 DOI: 10.3389/fimmu.2023.1145649] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/07/2023] [Indexed: 04/11/2023] Open
Abstract
C1q is a crucial component of the complement system, which is activated through the classical pathway to perform non-specific immune functions, serving as the first line of defense against pathogens. C1q can also bind to specific receptors to carry out immune and other functions, playing a vital role in maintaining immune homeostasis and normal physiological functions. In the developing central nervous system (CNS), C1q functions in synapse formation and pruning, serving as a key player in the development and homeostasis of neuronal networks in the CNS. C1q has a close relationship with microglia and astrocytes, and under their influence, C1q may contribute to the development of CNS disorders. Furthermore, C1q can also have independent effects on neurological disorders, producing either beneficial or detrimental outcomes. Most of the evidence for these functions comes from animal models, with some also from human specimen studies. C1q is now emerging as a promising target for the treatment of a variety of diseases, and clinical trials are already underway for CNS disorders. This article highlights the role of C1q in CNS diseases, offering new directions for the diagnosis and treatment of these conditions.
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Affiliation(s)
- Wenjie Zhang
- Department of Emergency Intensive Care Unit, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of General Practice, Xingyang Sishui Central Health Center, Zhengzhou, China
| | - Yuan Chen
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hui Pei
- Department of Emergency Intensive Care Unit, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Cai H, Pang Y, Wang Q, Qin W, Wei C, Li Y, Li T, Li F, Wang Q, Li Y, Wei Y, Jia L. Proteomic profiling of circulating plasma exosomes reveals novel biomarkers of Alzheimer's disease. Alzheimers Res Ther 2022; 14:181. [PMID: 36471423 PMCID: PMC9720984 DOI: 10.1186/s13195-022-01133-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/25/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Neuronal- and astrocyte-derived exosomes have been identified as an optimal source for screening biomarkers for Alzheimer's disease (AD). However, few studies focus on the bulk exosome population isolated from plasma of AD. This study investigated whether proteins in bulk exosomes can aid in the diagnosis of AD. METHODS The plasma exosomes were collected by ultracentrifuge. Protein samples were extracted from exosomes. Cerebrospinal fluid levels of amyloid β (Aβ)42 and phosphorylated tau (P-tau)181 were measured for diagnostic purposes. A pilot study (controls, 20; AD, 20) followed by a second dataset (controls, 56; AD, 58) was used to establish a diagnostic model of AD. Mass spectrometry-based proteomics was performed to profile the plasma exosomal proteome. Parallel reaction monitoring was used to further confirm the differentially expressed proteins. RESULTS In total, 328 proteins in plasma exosomes were quantified. Among them, 31 proteins were altered in AD patients, and 12 were validated. The receiver operating characteristic curve analysis revealed a combination of six proteins (upregulated: Ig-like domain-containing protein (A0A0G2JRQ6), complement C1q subcomponent subunit C (C1QC), complement component C9 (CO9), platelet glycoprotein Ib beta chain (GP1BB), Ras suppressor protein 1 (RSU1); downregulated: disintegrin and metalloproteinase domain 10 (ADA10)) has the capacity to differentiate AD patients from healthy controls with high accuracy. Linear correlation analysis showed that the combination was significantly correlated with cognitive performance. CONCLUSIONS The combination of plasma exosomal proteins A0A0G2JRQ6, C1QC, CO9, GP1BB, RSU1, and ADA10 acts as a novel candidate biomarker to differentiate AD patients from healthy individuals.
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Affiliation(s)
- Huimin Cai
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Yana Pang
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Qi Wang
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Wei Qin
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Cuibai Wei
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Ying Li
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Tingting Li
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Fangyu Li
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Qigeng Wang
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Yan Li
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Yiping Wei
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
| | - Longfei Jia
- grid.24696.3f0000 0004 0369 153XInnovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, 100000 China
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Chen M, Jia S, Xue M, Huang H, Xu Z, Yang D, Zhu W, Song Q. Dual-Stream Subspace Clustering Network for revealing gene targets in Alzheimer's disease. Comput Biol Med 2022; 151:106305. [PMID: 36401971 DOI: 10.1016/j.compbiomed.2022.106305] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 11/02/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
The rapid development of scRNA-seq technology in recent years has enabled us to capture high-throughput gene expression profiles at single-cell resolution, reveal the heterogeneity of complex cell populations, and greatly advance our understanding of the underlying mechanisms in human diseases. Traditional methods for gene co-expression clustering are limited to discovering effective gene groups in scRNA-seq data. In this paper, we propose a novel gene clustering method based on convolutional neural networks called Dual-Stream Subspace Clustering Network (DS-SCNet). DS-SCNet can accurately identify important gene clusters from large scales of single-cell RNA-seq data and provide useful information for downstream analysis. Based on the simulated datasets, DS-SCNet successfully clusters genes into different groups and outperforms mainstream gene clustering methods, such as DBSCAN and DESC, across different evaluation metrics. To explore the biological insights of our proposed method, we applied it to real scRNA-seq data of patients with Alzheimer's disease (AD). DS-SCNet analyzed the single-cell RNA-seq data with 10,850 genes, and accurately identified 8 optimal clusters from 6673 cells. Enrichment analysis of these gene clusters revealed functional signaling pathways including the ILS signaling, the Rho GTPase signaling, and hemostasis pathways. Further analysis of gene regulatory networks identified new hub genes such as ELF4 as important regulators of AD, which indicates that DS-SCNet contributes to the discovery and understanding of the pathogenesis in Alzheimer's disease.
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Affiliation(s)
- Minghan Chen
- Department of Computer Science, Wake Forest University, Winston-Salem, NC, USA
| | - Shishen Jia
- School of Automation, Hangzhou Dianzi University, Hangzhou, Zhejiang, China
| | - Mengfan Xue
- School of Automation, Hangzhou Dianzi University, Hangzhou, Zhejiang, China; Zhejiang Lab, Hangzhou, Zhejiang, China
| | | | - Ziang Xu
- Department of Computer Science, Wake Forest University, Winston-Salem, NC, USA
| | - Defu Yang
- Zhejiang Lab, Hangzhou, Zhejiang, China
| | - Wentao Zhu
- Zhejiang Lab, Hangzhou, Zhejiang, China.
| | - Qianqian Song
- Center for Cancer Genomics and Precision Oncology, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston Salem, NC, USA; Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, USA.
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36
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Gomez-Arboledas A, Carvalho K, Balderrama-Gutierrez G, Chu SH, Liang HY, Schartz ND, Selvan P, Petrisko TJ, Pan MA, Mortazavi A, Tenner AJ. C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimer's disease. Acta Neuropathol Commun 2022; 10:116. [PMID: 35978440 PMCID: PMC9386996 DOI: 10.1186/s40478-022-01416-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/29/2022] [Indexed: 11/10/2022] Open
Abstract
Multiple studies have recognized the involvement of the complement cascade during Alzheimer’s disease pathogenesis. However, the specific role of C5a-C5aR1 signaling in the progression of this neurodegenerative disease is still not clear. Furthermore, its potential as a therapeutic target to treat AD still remains to be elucidated. Canonically, generation of the anaphylatoxin C5a as the result of complement activation and interaction with its receptor C5aR1 triggers a potent inflammatory response. Previously, genetic ablation of C5aR1 in a mouse model of Alzheimer’s disease exerted a protective effect by preventing cognitive deficits. Here, using PMX205, a potent, specific C5aR1 antagonist, in the Tg2576 mouse model of Alzheimer’s disease we show a striking reduction in dystrophic neurites in parallel with the reduced amyloid load, rescue of the excessive pre-synaptic loss associated with AD cognitive impairment and the polarization of microglial gene expression towards a DAM-like phenotype that are consistent with the neuroprotective effects seen. These data support the beneficial effect of a pharmacological inhibition of C5aR1 as a promising therapeutic approach to treat Alzheimer’s disease. Supportive of the safety of this treatment is the recent FDA-approval of another other C5a receptor 1 antagonist, Avacopan, as a treatment for autoimmune inflammatory diseases.
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Affiliation(s)
- Angela Gomez-Arboledas
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA
| | - Klebea Carvalho
- Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA
| | | | - Shu-Hui Chu
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA
| | - Heidi Yahan Liang
- Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA
| | - Nicole D Schartz
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA
| | - Purnika Selvan
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA
| | - Tiffany J Petrisko
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA
| | - Miranda A Pan
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA
| | - Ali Mortazavi
- Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA
| | - Andrea J Tenner
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. .,Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA. .,Department of Pathology and Experimental Medicine, University of California Irvine, Irvine, CA, USA.
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Saez-Calveras N, Stuve O. The role of the complement system in Multiple Sclerosis: A review. Front Immunol 2022; 13:970486. [PMID: 36032156 PMCID: PMC9399629 DOI: 10.3389/fimmu.2022.970486] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
The complement system has been involved in the pathogenesis of multiple neuroinflammatory and neurodegenerative conditions. In this review, we evaluated the possible role of complement activation in multiple sclerosis (MS) with a focus in progressive MS, where the disease pathogenesis remains to be fully elucidated and treatment options are limited. The evidence for the involvement of the complement system in the white matter plaques and gray matter lesions of MS stems from immunohistochemical analysis of post-mortem MS brains, in vivo serum and cerebrospinal fluid biomarker studies, and animal models of Experimental Autoimmune Encephalomyelitis (EAE). Complement knock-out studies in these animal models have revealed that this system may have a “double-edge sword” effect in MS. On the one hand, complement proteins may aid in promoting the clearance of myelin degradation products and other debris through myeloid cell-mediated phagocytosis. On the other, its aberrant activation may lead to demyelination at the rim of progressive MS white matter lesions as well as synapse loss in the gray matter. The complement system may also interact with known risk factors of MS, including as Epstein Barr Virus (EBV) infection, and perpetuate the activation of CNS self-reactive B cell populations. With the mounting evidence for the involvement of complement in MS, the development of complement modulating therapies for this condition is appealing. Herein, we also reviewed the pharmacological complement inhibitors that have been tested in MS animal models as well as in clinical trials for other neurologic diseases. The potential use of these agents, such as the C5-binding antibody eculizumab in MS will require a detailed understanding of the role of the different complement effectors in this disease and the development of better CNS delivery strategies for these compounds.
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Affiliation(s)
- Nil Saez-Calveras
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Olaf Stuve
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
- Neurology Section, Veterans Affairs (VA) North Texas Health Care System, Dallas, TX, United States
- *Correspondence: Olaf Stuve,
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Schulz K, Trendelenburg M. C1q as a target molecule to treat human disease: What do mouse studies teach us? Front Immunol 2022; 13:958273. [PMID: 35990646 PMCID: PMC9385197 DOI: 10.3389/fimmu.2022.958273] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/24/2022] [Indexed: 11/17/2022] Open
Abstract
The complement system is a field of growing interest for pharmacological intervention. Complement protein C1q, the pattern recognition molecule at the start of the classical pathway of the complement cascade, is a versatile molecule with additional non-canonical actions affecting numerous cellular processes. Based on observations made in patients with hereditary C1q deficiency, C1q is protective against systemic autoimmunity and bacterial infections. Accordingly, C1q deficient mice reproduce this phenotype with susceptibility to autoimmunity and infections. At the same time, beneficial effects of C1q deficiency on disease entities such as neurodegenerative diseases have also been described in murine disease models. This systematic review provides an overview of all currently available literature on the C1q knockout mouse in disease models to identify potential target diseases for treatment strategies focusing on C1q, and discusses potential side-effects when depleting and/or inhibiting C1q.
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Affiliation(s)
- Kristina Schulz
- Laboratory of Clinical Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
- *Correspondence: Kristina Schulz,
| | - Marten Trendelenburg
- Laboratory of Clinical Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
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Linzey M, DiSano K, Welsh N, Pachner A, Gilli F. Divergent complement system activation in two clinically distinct murine models of multiple sclerosis. Front Immunol 2022; 13:924734. [PMID: 35958570 PMCID: PMC9360327 DOI: 10.3389/fimmu.2022.924734] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/01/2022] [Indexed: 12/30/2022] Open
Abstract
Multiple sclerosis (MS) is a neurological disease featuring neuroinflammation and neurodegeneration in young adults. So far, most research has focused on the peripheral immune system, which appears to be the driver of acute relapses. Concurrently, the mechanisms underlying neurodegeneration in the progressive forms of the disease remain unclear. The complement system, a molecular component of the innate immunity, has been recently implicated in several neurological disorders, including MS. However, it is still unknown if the complement proteins detected in the central nervous system (CNS) are actively involved in perpetuating chronic inflammation and neurodegeneration. To address this knowledge gap, we compared two clinically distinct mouse models of MS: 1) proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (rEAE) resembling a relapsing-remitting disease course, and 2) Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) resembling a progressive disease. Real-time PCR was performed in the spinal cord of rEAE mice, TMEV-IDD mice and age-matched sham controls to quantify gene expression for a broad range of complement components. In both experimental models, we found significantly increased expression of complement factors, such as C1q, C3, CfB, and C3aR. We showed that the complement system, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of C1q, C3 and C3aR1 were all significantly correlated to a worse disease outcome (all P≤0.0168). In line with this finding, C1q and C3 deposition was observed in the spinal cord of TMEV-IDD mice. Furthermore, C1q deposition was detected in spinal cord regions characterized by inflammation, demyelination, and axonal damage. Conversely, activation of the classical complement cascade seemed to result in protection from rEAE (C1q: P=0.0307). Interestingly, the alternative pathway related to a worse disease outcome in rEAE (CFb: P=0.0006). Overall, these results indicate potential divergent roles for the complement system in MS. The chronic-progressive disease form is more reliant on the activation of the classic complement pathway, while protecting from acute relapses. Conversely, relapsing MS appears more likely affected by the alternative pathway. Understanding the functions of the complement system in MS is critical and can lead to better, more targeted therapies in the future.
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Affiliation(s)
- Michael Linzey
- Department of Neurology at Dartmouth Hitchcock Medical Center, Lebanon, NH, United States
- Integrative Neuroscience at Dartmouth, Dartmouth College, Hanover, NH, United States
- *Correspondence: Michael Linzey,
| | - Krista DiSano
- Department of Neurology at Dartmouth Hitchcock Medical Center, Lebanon, NH, United States
- Department of Veteran Affairs Medical Center, White River Junction, VT, United States
| | - Nora Welsh
- Department of Neurology at Dartmouth Hitchcock Medical Center, Lebanon, NH, United States
- Integrative Neuroscience at Dartmouth, Dartmouth College, Hanover, NH, United States
| | - Andrew Pachner
- Department of Neurology at Dartmouth Hitchcock Medical Center, Lebanon, NH, United States
| | - Francesca Gilli
- Department of Neurology at Dartmouth Hitchcock Medical Center, Lebanon, NH, United States
- Integrative Neuroscience at Dartmouth, Dartmouth College, Hanover, NH, United States
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Carpanini SM, Torvell M, Bevan RJ, Byrne RAJ, Daskoulidou N, Saito T, Saido TC, Taylor PR, Hughes TR, Zelek WM, Morgan BP. Terminal complement pathway activation drives synaptic loss in Alzheimer's disease models. Acta Neuropathol Commun 2022; 10:99. [PMID: 35794654 PMCID: PMC9258209 DOI: 10.1186/s40478-022-01404-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/29/2022] [Indexed: 11/23/2022] Open
Abstract
Complement is involved in developmental synaptic pruning and pathological synapse loss in Alzheimer's disease. It is posited that C1 binding initiates complement activation on synapses; C3 fragments then tag them for microglial phagocytosis. However, the precise mechanisms of complement-mediated synaptic loss remain unclear, and the role of the lytic membrane attack complex (MAC) is unexplored. We here address several knowledge gaps: (i) is complement activated through to MAC at the synapse? (ii) does MAC contribute to synaptic loss? (iii) can MAC inhibition prevent synaptic loss? Novel methods were developed and optimised to quantify C1q, C3 fragments and MAC in total and regional brain homogenates and synaptoneurosomes from WT and AppNL-G-F Alzheimer's disease model mouse brains at 3, 6, 9 and 12 months of age. The impact on synapse loss of systemic treatment with a MAC blocking antibody and gene knockout of a MAC component was assessed in Alzheimer's disease model mice. A significant increase in C1q, C3 fragments and MAC was observed in AppNL-G-F mice compared to controls, increasing with age and severity. Administration of anti-C7 antibody to AppNL-G-F mice modulated synapse loss, reflected by the density of dendritic spines in the vicinity of plaques. Constitutive knockout of C6 significantly reduced synapse loss in 3xTg-AD mice. We demonstrate that complement dysregulation occurs in Alzheimer's disease mice involving the activation (C1q; C3b/iC3b) and terminal (MAC) pathways in brain areas associated with pathology. Inhibition or ablation of MAC formation reduced synapse loss in two Alzheimer's disease mouse models, demonstrating that MAC formation is a driver of synapse loss. We suggest that MAC directly damages synapses, analogous to neuromuscular junction destruction in myasthenia gravis.
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Affiliation(s)
- Sarah M Carpanini
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Megan Torvell
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Ryan J Bevan
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Robert A J Byrne
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Nikoleta Daskoulidou
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Takashi Saito
- Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takaomi C Saido
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Japan
| | - Philip R Taylor
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Timothy R Hughes
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Wioleta M Zelek
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - B Paul Morgan
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
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Proteomics for comprehensive characterization of extracellular vesicles in neurodegenerative disease. Exp Neurol 2022; 355:114149. [PMID: 35732219 DOI: 10.1016/j.expneurol.2022.114149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 01/28/2022] [Accepted: 06/15/2022] [Indexed: 11/22/2022]
Abstract
Extracellular vesicles (EVs) are small lipid bilayer particles ubiquitously released by almost every cell type. A specific and selective constituents of EVs loaded with variety of proteins, lipids, small noncoding RNAs, and long non-coding RNAs are reflective of cellular events, type, and physiologic/pathophysiologic status of the cell of origin. Moreover, these molecular contents carry information from the cell of origin to recipient cells, modulating intercellular communication. Recent studies demonstrated that EVs not only play a neuroprotective role by mediating the removal of toxic proteins, but also emerge as an important player in various neurodegenerative disease onset and progression through facilitating of misfolded proteins propagation. For this reason, neurodegenerative disease-associated differences in EV proteome relative to normal EVs can be used to fulfil diagnostic, prognostic, and therapeutic purposes. Nonetheless, characterizing EV proteome obtained from biological samples (brain tissue and body fluids, including urea, blood, saliva, and CSF) is a challenging task. Herein, we review the status of EV proteome profiling and the updated discovery of potential biomarkers for the diagnosis of neurodegenerative disease with an emphasis on the integration of high-throughput advanced mass spectrometry (MS) technologies for both qualitative and quantitative analysis of EVs in different clinical tissue/body fluid samples in past five years.
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Vadászi H, Kiss B, Micsonai A, Schlosser G, Szaniszló T, Kovács RÁ, Györffy BA, Kékesi KA, Goto Y, Uzonyi B, Liliom K, Kardos J. Competitive inhibition of the classical complement pathway using exogenous single-chain C1q recognition proteins. J Biol Chem 2022; 298:102113. [PMID: 35690144 PMCID: PMC9270254 DOI: 10.1016/j.jbc.2022.102113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 06/03/2022] [Accepted: 06/06/2022] [Indexed: 11/26/2022] Open
Abstract
Complement component 1q (C1q) is a protein complex of the innate immune system with well-characterized binding partners that constitutes part of the classical complement pathway (CP). In addition, C1q was recently described in the central nervous system as having a role in synapse elimination both in the healthy brain and in neurodegenerative diseases. However, the molecular mechanism of C1q-associated synapse phagocytosis is still unclear. Here, we designed monomer and multimer protein constructs which comprised the globular interaction recognition parts of mouse C1q (gC1q) as single-chain molecules (sc-gC1q proteins) lacking the collagen-like effector region. These molecules, which can competitively inhibit the function of C1q, were expressed in an E. coli expression system, and their structure and capabilities to bind known CP activators were validated by mass spectrometry, analytical size exclusion chromatography, analytical ultracentrifugation, circular dichroism spectroscopy, and ELISA. We further characterized the interactions between these molecules and immunoglobulins and neuronal pentraxins using surface plasmon resonance spectroscopy. We demonstrated that sc-gC1qs potently inhibited the function of C1q. Furthermore, these sc-gC1qs competed with C1q in binding to the embryonal neuronal cell membrane. We conclude that the application of sc-gC1qs can reveal neuronal localization and functions of C1q in assays in vivo and might serve as a basis for engineering inhibitors for therapeutic purposes.
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Affiliation(s)
- Henrietta Vadászi
- ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Bence Kiss
- Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - András Micsonai
- ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Gitta Schlosser
- MTA ELTE Lendu¨let Ion Mobility Mass Spectrometry Research Group, Department of Analytical Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Tamás Szaniszló
- Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Réka Á Kovács
- ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Balázs A Györffy
- ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Katalin A Kékesi
- ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary; Department of Physiology and Neurobiology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Yuji Goto
- Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
| | - Barbara Uzonyi
- Department of Immunology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary; MTA-ELTE Complement Research Group, Eötvös Loránd Research Network (ELKH), Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Károly Liliom
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - József Kardos
- ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary.
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Complement as a powerful "influencer" in the brain during development, adulthood and neurological disorders. Adv Immunol 2021; 152:157-222. [PMID: 34844709 DOI: 10.1016/bs.ai.2021.09.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The complement system was long considered as only a powerful effector arm of the immune system that, while critically protective, could lead to inflammation and cell death if overactivated, even in the central nervous system (CNS). However, in the past decade it has been recognized as playing critical roles in key physiological processes in the CNS, including neurogenesis and synaptic remodeling in the developing and adult brain. Inherent in these processes are the interactions with cells in the brain, and the cascade of interactions and functional consequences that ensue. As a result, investigations of therapeutic approaches for both suppressing excessive complement driven neurotoxicity and aberrant sculpting of neuronal circuits, require broad (and deep) knowledge of the functional activities of multiple components of this highly evolved and regulated system to avoid unintended negative consequences in the clinic. Advances in basic science are beginning to provide a roadmap for translation to therapeutics, with both small molecule and biologics. Here, we present examples of the critical roles of proper complement function in the development and sculpting of the nervous system, and in enabling rapid protection from infection and clearance of dying cells. Microglia are highlighted as important command centers that integrate signals from the complement system and other innate sensors that are programed to provide support and protection, but that direct detrimental responses to aberrant activation and/or regulation of the system. Finally, we present promising research areas that may lead to effective and precision strategies for complement targeted interventions to promote neurological health.
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Peterson SL, Li Y, Sun CJ, Wong KA, Leung KS, de Lima S, Hanovice NJ, Yuki K, Stevens B, Benowitz LI. Retinal Ganglion Cell Axon Regeneration Requires Complement and Myeloid Cell Activity within the Optic Nerve. J Neurosci 2021; 41:8508-8531. [PMID: 34417332 PMCID: PMC8513703 DOI: 10.1523/jneurosci.0555-21.2021] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/21/2021] [Accepted: 08/16/2021] [Indexed: 01/01/2023] Open
Abstract
Axon regenerative failure in the mature CNS contributes to functional deficits following many traumatic injuries, ischemic injuries, and neurodegenerative diseases. The complement cascade of the innate immune system responds to pathogen threat through inflammatory cell activation, pathogen opsonization, and pathogen lysis, and complement is also involved in CNS development, neuroplasticity, injury, and disease. Here, we investigated the involvement of the classical complement cascade and microglia/monocytes in CNS repair using the mouse optic nerve injury (ONI) model, in which axons arising from retinal ganglion cells (RGCs) are disrupted. We report that central complement C3 protein and mRNA, classical complement C1q protein and mRNA, and microglia/monocyte phagocytic complement receptor CR3 all increase in response to ONI, especially within the optic nerve itself. Importantly, genetic deletion of C1q, C3, or CR3 attenuates RGC axon regeneration induced by several distinct methods, with minimal effects on RGC survival. Local injections of C1q function-blocking antibody revealed that complement acts primarily within the optic nerve, not retina, to support regeneration. Moreover, C1q opsonizes and CR3+ microglia/monocytes phagocytose growth-inhibitory myelin debris after ONI, a likely mechanism through which complement and myeloid cells support axon regeneration. Collectively, these results indicate that local optic nerve complement-myeloid phagocytic signaling is required for CNS axon regrowth, emphasizing the axonal compartment and highlighting a beneficial neuroimmune role for complement and microglia/monocytes in CNS repair.SIGNIFICANCE STATEMENT Despite the importance of achieving axon regeneration after CNS injury and the inevitability of inflammation after such injury, the contributions of complement and microglia to CNS axon regeneration are largely unknown. Whereas inflammation is commonly thought to exacerbate the effects of CNS injury, we find that complement proteins C1q and C3 and microglia/monocyte phagocytic complement receptor CR3 are each required for retinal ganglion cell axon regeneration through the injured mouse optic nerve. Also, whereas studies of optic nerve regeneration generally focus on the retina, we show that the regeneration-relevant role of complement and microglia/monocytes likely involves myelin phagocytosis within the optic nerve. Thus, our results point to the importance of the innate immune response for CNS repair.
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Affiliation(s)
- Sheri L Peterson
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
- F.M. Kirby Neurobiology Center, and
- Department of Neurosurgery and
| | - Yiqing Li
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
- F.M. Kirby Neurobiology Center, and
- Department of Neurosurgery and
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong China, 510060
| | - Christina J Sun
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
| | - Kimberly A Wong
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
- F.M. Kirby Neurobiology Center, and
- Department of Neurosurgery and
| | - Kylie S Leung
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
| | - Silmara de Lima
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
- F.M. Kirby Neurobiology Center, and
- Department of Neurosurgery and
| | - Nicholas J Hanovice
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
- F.M. Kirby Neurobiology Center, and
- Department of Neurosurgery and
| | - Kenya Yuki
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
- F.M. Kirby Neurobiology Center, and
- Department of Neurosurgery and
| | - Beth Stevens
- F.M. Kirby Neurobiology Center, and
- Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115
- Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142
| | - Larry I Benowitz
- Laboratories for Neuroscience Research in Neurosurgery
- Department of Neurosurgery
- F.M. Kirby Neurobiology Center, and
- Department of Neurosurgery and
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02115
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45
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Gomez-Arboledas A, Acharya MM, Tenner AJ. The Role of Complement in Synaptic Pruning and Neurodegeneration. Immunotargets Ther 2021; 10:373-386. [PMID: 34595138 PMCID: PMC8478425 DOI: 10.2147/itt.s305420] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 09/04/2021] [Indexed: 12/14/2022] Open
Abstract
The complement system, an essential part of the innate immune system, is composed of a group of secreted and membrane proteins that collectively participate in maintaining the function of the healthy and diseased brain. However, an inappropriate activation of the complement system has been related to an inflammatory response in multiple diseases, such as stroke, traumatic brain injury, multiple sclerosis, and Alzheimer's disease, as well as Zika infection and radiotherapy. In addition, C1q and C3 (initial activation components of the complement cascade) have been shown to play a key beneficial role in the refinement of synaptic circuits during developmental stages and adult plasticity. Nevertheless, excessive synaptic pruning in the adult brain can be detrimental and has been associated with synaptic loss in several pathological conditions. In this brief review, we will discuss the role of the complement system in synaptic pruning as well as its contribution to neurodegeneration and cognitive deficits. We also mention potential therapeutic approaches to target the complement system to treat several neuroinflammatory diseases and unintended consequences of radiotherapy.
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Affiliation(s)
- Angela Gomez-Arboledas
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Munjal M Acharya
- Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA
- Department of Radiation Oncology, University of California, Irvine, Irvine, CA, USA
| | - Andrea J Tenner
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
- Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA
- Department of Pathology and Laboratory Medicine, University of California, Irvine, School of Medicine, Irvine, CA, USA
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46
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Holden SS, Grandi FC, Aboubakr O, Higashikubo B, Cho FS, Chang AH, Forero AO, Morningstar AR, Mathur V, Kuhn LJ, Suri P, Sankaranarayanan S, Andrews-Zwilling Y, Tenner AJ, Luthi A, Aronica E, Ryan Corces M, Yednock T, Paz JT. Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury. Science 2021; 373:eabj2685. [PMID: 34516796 PMCID: PMC8750918 DOI: 10.1126/science.abj2685] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Although traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild TBI (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic system. Increased C1q expression colocalized with neuron loss and chronic inflammation and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are a source of thalamic C1q. The corticothalamic circuit could thus be a new target for treating TBI-related disabilities.
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Affiliation(s)
- Stephanie S Holden
- Neurosciences Graduate Program, University of California, San Francisco, San Francisco CA 94158, USA
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
- Department of Neurology, University of California, San Francisco, San Francisco CA 94158, USA
| | - Fiorella C Grandi
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
- Department of Neurology, University of California, San Francisco, San Francisco CA 94158, USA
| | - Oumaima Aboubakr
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
| | - Bryan Higashikubo
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
| | - Frances S Cho
- Neurosciences Graduate Program, University of California, San Francisco, San Francisco CA 94158, USA
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
- Department of Neurology, University of California, San Francisco, San Francisco CA 94158, USA
| | - Andrew H Chang
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
| | | | - Allison R. Morningstar
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
| | - Vidhu Mathur
- Annexon Biosciences, South San Francisco CA 94080, USA
| | - Logan J Kuhn
- Annexon Biosciences, South San Francisco CA 94080, USA
| | - Poojan Suri
- Annexon Biosciences, South San Francisco CA 94080, USA
| | | | | | - Andrea J. Tenner
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA
| | - Anita Luthi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Eleonora Aronica
- Department of Neuropathology, Amsterdam UMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
- Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands
| | - M. Ryan Corces
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
- Department of Neurology, University of California, San Francisco, San Francisco CA 94158, USA
| | - Ted Yednock
- Annexon Biosciences, South San Francisco CA 94080, USA
| | - Jeanne T Paz
- Neurosciences Graduate Program, University of California, San Francisco, San Francisco CA 94158, USA
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA 94158, USA
- Department of Neurology, University of California, San Francisco, San Francisco CA 94158, USA
- The Kavli Institute for Fundamental Neuroscience, and The Weill Institute for Neurosciences, University of California San Francisco, San Francisco CA 94158, USA
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47
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Biringer RG. Endocannabinoid signaling pathways: beyond CB1R and CB2R. J Cell Commun Signal 2021; 15:335-360. [PMID: 33978927 PMCID: PMC8222499 DOI: 10.1007/s12079-021-00622-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/27/2021] [Indexed: 12/15/2022] Open
Abstract
The search for cannabinoid receptors other than CB1R and CB2R has been ongoing for over a decade. A number of orphan receptors have been proposed as potential cannabinoid receptors primarily based on phylogenic arguments and reactivity towards known endocannabinoids and phytocannabinoids. Seven putative cannabinoid receptors are described and discussed, and evidence for and against their inclusion in this category are presented.
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Affiliation(s)
- Roger Gregory Biringer
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
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48
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Chen MM, Hu ZL, Ding JH, Du RH, Hu G. Astrocytic Kir6.1 deletion aggravates neurodegeneration in the lipopolysaccharide-induced mouse model of Parkinson's disease via astrocyte-neuron cross talk through complement C3-C3R signaling. Brain Behav Immun 2021; 95:310-320. [PMID: 33838249 DOI: 10.1016/j.bbi.2021.04.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/19/2021] [Accepted: 04/03/2021] [Indexed: 12/17/2022] Open
Abstract
Complement pathway over-activation has been implicated in a variety of neurological diseases. However, the signaling pathways governing astrocytic complement activation in Parkinson's disease (PD) are poorly understood. Kir6.1, a pore-forming subunit of ATP-sensitive potassium (K-ATP) channel, is prominently expressed in astrocytes and exhibits anti-inflammatory effects. Therefore, we hypothesize that Kir6.1/K-ATP channel may regulate astrocytic complement activation in the pathogenesis of PD. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on astrocytic complement activation triggered by the lipopolysaccharide (LPS). Here, we found that astrocytic Kir6.1 KO mice showed more dopaminergic neuron loss and more astrocyte reactivity in substantia nigra compacta than controls. We also found that astrocytic Kir6.1 KO increased the expression of complement C3 in astrocytes in LPS-induced mouse model of PD. Mechanistically, astrocytic Kir6.1 KO promoted astroglial NF-κB activation to elicit extracellular release of C3, which in turn interacted with neuronal C3aR to induce neuron death. Blocking complement function by NF-κB inhibitor or C3aR antagonist rescued the aggravated neuron death induced by Kir6.1 KO. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel prevents neurodegeneration in PD via astrocyte-neuron cross talk through NF-κB/C3/C3aR signaling and suggest that targeting astroglial Kir6.1/K-ATP channel-NF-κB-C3-neuronal C3aR signaling represents a novel therapeutic strategy for PD.
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Affiliation(s)
- Miao-Miao Chen
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China
| | - Zhao-Li Hu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China
| | - Jian-Hua Ding
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China
| | - Ren-Hong Du
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China.
| | - Gang Hu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China; Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, PR China.
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49
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Potential and Limits of Cannabinoids in Alzheimer's Disease Therapy. BIOLOGY 2021; 10:biology10060542. [PMID: 34204237 PMCID: PMC8234911 DOI: 10.3390/biology10060542] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 11/16/2022]
Abstract
Simple Summary This review was aimed at exploring the potentiality of drugging the endocannabinoid system as a therapeutic option for Alzheimer’s disease (AD). Recent discoveries have demonstrated how the modulation of cannabinoid receptor 1 (CB1) and receptor 2 (CB2) can exert neuroprotective effects without the recreational and pharmacological properties of Cannabis sativa. Thus, this review explores the potential of cannabinoids in AD, also highlighting their limitations in perspective to point out the need for further research on cannabinoids in AD therapy. Abstract Alzheimer’s disease (AD) is a detrimental brain disorder characterized by a gradual cognitive decline and neuronal deterioration. To date, the treatments available are effective only in the early stage of the disease. The AD etiology has not been completely revealed, and investigating new pathological mechanisms is essential for developing effective and safe drugs. The recreational and pharmacological properties of marijuana are known for centuries, but only recently the scientific community started to investigate the potential use of cannabinoids in AD therapy—sometimes with contradictory outcomes. Since the endocannabinoid system (ECS) is highly expressed in the hippocampus and cortex, cannabis use/abuse has often been associated with memory and learning dysfunction in vulnerable individuals. However, the latest findings in AD rodent models have shown promising effects of cannabinoids in reducing amyloid plaque deposition and stimulating hippocampal neurogenesis. Beneficial effects on several dementia-related symptoms have also been reported in clinical trials after cannabinoid treatments. Accordingly, future studies should address identifying the correct therapeutic dosage and timing of treatment from the perspective of using cannabinoids in AD therapy. The present paper aims to summarize the potential and limitations of cannabinoids as therapeutics for AD, focusing on recent pre-clinical and clinical evidence.
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50
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Byrne RAJ, Torvell M, Daskoulidou N, Fathalla D, Kokkali E, Carpanini SM, Morgan BP. Novel Monoclonal Antibodies Against Mouse C1q: Characterisation and Development of a Quantitative ELISA for Mouse C1q. Mol Neurobiol 2021; 58:4323-4336. [PMID: 34002346 PMCID: PMC8487419 DOI: 10.1007/s12035-021-02419-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/30/2021] [Indexed: 12/20/2022]
Abstract
Recent studies have identified roles for complement in synaptic pruning, both physiological during development and pathological in Alzheimer's disease (AD). These reports suggest that C1q initiates complement activation on synapses and C3 fragments then tag them for removal by microglia. There is an urgent need to characterise these processes in rodent AD models; this requires the development of reagents and methods for detection and quantification of rodent C1q in fluids and pathological tissues. These will enable better evaluation of the role of C1q in disease and its value as disease biomarker. We describe the generation in C1q-deficient mice of novel monoclonal antibodies against mouse and rat C1q that enabled development of a sensitive, specific, and quantitative ELISA for mouse and rat C1q capable of measuring C1q in biological fluids and tissue extracts. Serum C1q levels were measured in wild-type (WT), C1q knockout (KO), C3 KO, C7 KO, Crry KO, and 3xTg and APPNL-G-F AD model mice through ageing. C1q levels significantly decreased in WT, APPNL-G-F, and C7 KO mice with ageing. C1q levels were reduced in APPNL-G-F compared to WT at all ages and in 3xTg at 12 months; C3 KO and C7 KO, but not Crry KO mice, also demonstrated significantly lower C1q levels compared to matched WT. In brain homogenates, C1q levels increased with age in both WT and APPNL-G-F mice. This robust and adaptable assay for quantification of mouse and rat C1q provides a vital tool for investigating the expression of C1q in rodent models of AD and other complement-driven pathologies.
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Affiliation(s)
- Robert A J Byrne
- UK Dementia Research Institute Cardiff, Hadyn Ellis Building, Cardiff University, Maindy Road, Cardiff, CF244HQ, UK.,Division of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Heath Park, Cardiff, CF144XN, UK
| | - Megan Torvell
- UK Dementia Research Institute Cardiff, Hadyn Ellis Building, Cardiff University, Maindy Road, Cardiff, CF244HQ, UK.,Division of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Heath Park, Cardiff, CF144XN, UK
| | - Nikoleta Daskoulidou
- UK Dementia Research Institute Cardiff, Hadyn Ellis Building, Cardiff University, Maindy Road, Cardiff, CF244HQ, UK.,Division of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Heath Park, Cardiff, CF144XN, UK
| | - Dina Fathalla
- UK Dementia Research Institute Cardiff, Hadyn Ellis Building, Cardiff University, Maindy Road, Cardiff, CF244HQ, UK.,Division of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Heath Park, Cardiff, CF144XN, UK
| | - Eirini Kokkali
- School of Optometry and Visual Sciences, Cardiff University, Maindy Road, Cardiff, CF244HQ, UK
| | - Sarah M Carpanini
- UK Dementia Research Institute Cardiff, Hadyn Ellis Building, Cardiff University, Maindy Road, Cardiff, CF244HQ, UK.,Division of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Heath Park, Cardiff, CF144XN, UK
| | - B Paul Morgan
- UK Dementia Research Institute Cardiff, Hadyn Ellis Building, Cardiff University, Maindy Road, Cardiff, CF244HQ, UK. .,Division of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Heath Park, Cardiff, CF144XN, UK.
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