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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' 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

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.

项目概要/摘要 阿尔茨海默病（AD）是老年人中最常见的伴有痴呆的神经退行性疾病， 但该疾病的确切原因和潜在的致病机制导致开发有效的治疗方法 治疗干预措施尚未确定。最近，一系列遗传和转录组学研究 人类和动物模型强调了小胶质细胞在 AD 中的关键作用，并且可能具有缓解疾病的作用。一次 激活后，小胶质细胞能够表现出一系列表型，从稳态到 神经退行性表型，具有独特的转录组特征。但仍有待确定 哪些小胶质细胞亚群具有神经保护作用或有害，以及这种小胶质细胞激活是如何驱动的 什么细胞机制和疾病状况。我们有强有力的证据表明富含小胶质细胞的脾脏 酪氨酸激酶（SYK）关键控制小胶质细胞的激活模式。细胞中的 SYK 信号传导 小胶质细胞受到包括 TREM2 在内的多种细胞表面免疫受体的调节。机械细节 SYK 激活以及其频率、持续时间和激活模式如何确定上述内容 小胶质细胞的表型尚未阐明。在这里，我们建议检验我们的新假设：SYK 是 根据表达水平调节一系列小胶质细胞激活的关键分子中心 TREM2、年龄和 Aβ 病理阶段。当 SYK 的表达为 在小胶质细胞中具有生理作用，具有神经保护作用并促进有效抑制和去除 Aβ，而 SYK 的长期或慢性激活，特别是当其在小胶质细胞中表达升高时，是有害的 并驱动促炎和退行性激活。在这个建议中，我们首先会仔细调查 SYK 控制小胶质细胞各种表达的几个标志性功能的潜在机制 SYK 和野生型 TREM2 的水平，以及存在 TREM2 风险变异的情况。然后我们将使用一个 动物模型以确定 SYK 的二分激活是否取决于两个不同的 Aβ 斑块阶段 AD小鼠模型。为了检验我们的假设，我们提出了体外和体内研究的结合，利用 新型条件转基因小鼠模型和人 iPSC 衍生的小胶质细胞 (iMGL)。拟议的研究 将深入了解 SYK 激活和激活的小胶质细胞是否以及如何导致该疾病 AD 的进展。此外，该建议具有可行性、意义重大、与病因学高度相关。 AD 的发生和进展，我们相信其结果可能会对公共卫生产生巨大影响，同时 加速 AD 有效治疗方案的进展。