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Microglia dysregulation and SYK signaling in Alzheimer's disease

阿尔茨海默病中的小胶质细胞失调和 SYK 信号传导

基本信息

批准号：
10659670
负责人：
Masashi Kitazawa
金额：
$ 176.47万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659670
关键词：
Abeta clearance Acceleration Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Astrocytes Biochemical Brain Cell surface Cells Chronic Containment Data Dementia Development Disease Disease Progression Disease associated microglia Elderly Etiology Excision Exposure to Frequencies Genes Genetic Genetic Predisposition to Disease Genetic study Heterogeneity Human Human Genetics In Vitro Inflammatory Knowledge Late Onset Alzheimer Disease Ligands Mediating Microglia Molecular Morbidity - disease rate Mus Nerve Degeneration Neurodegenerative Disorders Outcome PLCG2 gene Pathogenesis Pathogenicity Pathologic Pathology Pattern Phagocytosis Phenotype Phosphotransferases Physiological Proliferating Public Health Research Role SYK gene Senile Plaques Signal Pathway Signal Transduction TREM2 gene Testing Therapeutic Therapeutic Intervention Transgenic Mice abeta accumulation genetic predictors glial activation human model improved in vivo in vivo Model induced pluripotent stem cell insight loss of function mortality mouse model neurodegenerative phenotype neuroinflammation neuron loss neuropathology neuroprotection neurotoxic novel overexpression risk variant tau Proteins tau aggregation therapeutically effective tool transcriptome transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with dementia among the elderly, yet exact causes of the disease and underlying pathogenic mechanisms that lead to development of effective therapeutic interventions have not been identified. Recently, a number of genetic and transcriptomic studies in humans and animal models highlight a critical, and possibly a disease-modifying role of microglia in AD. Once activated, microglia are capable of displaying a spectrum of phenotypes ranging from homeostatic to neurodegenerative phenotypes, with distinct transcriptomic signatures. However, it remains to be determined which subset(s) of microglia are neuroprotective or detrimental, and how such microglia activation is driven by what cellular mechanisms and disease conditions. We have strong evidence that microglia-enriched spleen tyrosine kinase (SYK) critically controls the activation pattern of microglia. The cellular SYK signaling in microglia is regulated by various cell-surface immunoreceptors including TREM2. The mechanistic details of SYK activation as well as how its frequency, duration and patterns of activation determine above-mentioned microglial phenotypes have not been elucidated. Here, we propose to test our novel hypothesis that SYK is the key molecular hub that regulates a spectrum of microglia activation depending on the expression levels of TREM2, age and the stage of Aβ pathology. We predict that activation of SYK, when its expression is physiological in microglia, is neuroprotective and promotes effective containment and removal of Aβ, whereas prolonged or chronic activation of SYK, especially when its expression is elevated in microglia, is detrimental and drives pro-inflammatory and degenerative activation. In this proposal, we will first carefully investigate the underlying mechanisms by which SYK controls several hallmark functions of microglia in various expression levels of SYK and wildtype TREM2, as well as in the presence of TREM2 risk variant. We will then use an animal model to determine if dichotomous activation of SYK depends on the Aβ plaque stages in two different mouse models of AD. To test our hypothesis, we propose a combination of in vitro and in vivo studies utilizing novel conditional transgenic mouse models and human iPSC-derived microglia (iMGL). The proposed research will provide insight into whether and how SYK activation and activated microglia contribute to the disease progression in AD. Furthermore, this proposal is feasible, highly-significant, and highly-relevant to the etiology and progression of AD and we believe that the outcomes could have large public health impact, while accelerating progress towards efficacious, therapeutic options for AD.

项目总结/文摘