Microglia dysregulation and SYK signaling in Alzheimer's disease

项目总结/摘要 阿尔茨海默病（AD）是老年人中最常见的神经退行性疾病， 然而，疾病的确切原因和潜在的致病机制，导致有效的发展， 尚未确定治疗干预措施。最近，一些遗传学和转录组学的研究， 人类和动物模型突出了小胶质细胞在AD中的关键作用，并且可能是疾病修饰作用。一旦 活化的小胶质细胞能够显示一系列表型， 神经退行性表型，具有不同的转录组学特征。然而， 小胶质细胞的哪些亚群是神经保护性的或有害的，以及这种小胶质细胞的激活是如何由 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）关键地控制小胶质细胞的活化模式。细胞SYK信号转导在 小胶质细胞受包括TREM 2在内的各种细胞表面免疫受体调节。机械细节 SYK激活及其频率、持续时间和激活模式如何决定上述 小神经胶质细胞表型尚未阐明。在这里，我们建议测试我们的新假设，SYK是 调节小胶质细胞激活的关键分子枢纽，取决于 TREM 2、年龄和Aβ病理分期。我们预测，当SYK的表达被激活时， 在小胶质细胞中生理性的，是神经保护性的，并促进有效的遏制和Aβ的去除，而 SYK的长期或慢性激活，特别是当其在小胶质细胞中的表达升高时， 并驱动促炎和退行性激活。在这份建议中，我们将首先仔细调查 SYK控制小胶质细胞在不同表达中的几种标志性功能的潜在机制 SYK和野生型TREM 2的水平，以及TREM 2风险变体的存在下。然后，我们将使用 动物模型，以确定SYK的二分激活是否取决于两种不同的Aβ斑块阶段 AD小鼠模型。为了验证我们的假设，我们提出了体外和体内研究的组合， 新的条件性转基因小鼠模型和人iPSC衍生的小胶质细胞（iMGL）。拟议研究 将提供深入了解是否以及如何SYK激活和激活的小胶质细胞有助于疾病 AD的进展。此外，这一建议是可行的，高度重要的，并与病因高度相关 我们相信这些结果可能会对公共卫生产生巨大的影响， 加速AD的有效治疗选择的进展。

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.