Augmenting AXL and MERTK function to restrain cognitive decline and improve health span in mouse models of Alzheimer's Disease

增强 AXL 和 MERTK 功能以抑制阿尔茨海默氏病小鼠模型的认知衰退并改善健康寿命

• 批准号: 10662677
• 负责人: Sourav Ghosh
• 金额: $ 239.22万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662677
• 关键词: Alzheimer' s disease model; Fibroblast Growth Factor; Impaired cognition; MERTK gene; healthspan; improved; mouse model; restraint

PROJECT SUMMARY/ABSTRACT A watershed moment in decades of research in Alzheimer's disease (AD) is the discovery that targeting certain molecules in microglial cells can improve a hitherto unknown functional mechanism in these cells, and arrest cognitive decline. The first in class of microglial molecular targets for AD therapy is TREM2. TREM2 expression is upregulated in microglia in the AD brain, the microglia changes from a homeostatic state to something known as damage-associated microglia (DAMs) as defined by transcriptomics, and the loss of TREM2 prevents DAM transition while accelerating disease progression. Notably, the loss of TREM2 prevents the upregulation of another microglial molecule - AXL. Whether AXL has a critical effector function in the DAM-mediated thwarting of cognitive decline remained heretofore unknown. We have discovered that augmenting AXL leads to the arrest of cognitive decline in a mouse model of AD. There is a potential third player in this axis - MERTK. MERTK has been implicated by an independent study (Huang et al., Nature Immunology, 2021) in the phagocytic engulfment of filamentous A[l by microglia and its eventual compaction into harmless dense core plaques. Here we propose a systematic approach to understand this still nebulous process of microglia-mediated arrest of cognitive decline. First, we will use mouse genetics to investigate the requirement of sequential involvement of TREM2, followed by AXL and likely subsequently by MERTK in microglia-mediated arrest of cognitive decline in mouse models of AD through behavioral tests and electrophysiological assessment of learning and memory. Second, we will correlate these genetic epistasis-associated functional changes in learning and memory to corresponding transcriptional state of microglia as assessed by single nucleus RNA sequencing. Our third aim is to evaluate cellular, subcellular, morphological and neuronal network level brain functional changes, including AD neuropathological hallmarks such as amyloid plaques and tau phosphorylation, as well as microglial functions such as phagocytosis and/or plaque barrier formation. We hypothesize that a TREM2, AXL and MERTK triad functions sequentially to engineer a beneficial microglia state, which in turn counters AD-associated ill-effects that manifest as cognitive decline. Therefore, augmenting the function of this triad would restrain cognitive decline and preserve brain health in AD. Our study could lead to the development of multivalent engagement of microglial molecules TREM2, AXL and MERTK, for novel therapeutics in AD.

项目摘要/摘要 几十年来，阿尔茨海默氏病（AD）的分水岭是针对一定的发现 小胶质细胞中的分子可以改善这些细胞中未知的功能机制，并阻止 认知能力下降。 AD疗法的小胶质细胞分子靶标的第一个是TREM2。 TREM2表达 在AD大脑的小胶质细胞中被上调，小胶质细胞从稳态状态变为已知的事物 作为由转录组学定义的损伤相关的小胶质细胞（大坝），而trem2的损失则阻止了大坝 在加速疾病进展的同时过渡。值得注意的是，trem2的损失阻止了上调 另一个小胶质分子-Axl。 AXL是否在大坝介导的挫败中具有关键的效应子功能 迄今为止，认知能力下降仍然未知。我们发现增强AXL导致逮捕 AD小鼠模型的认知能力下降。在此轴上有一个潜在的第三名球员-Mertk。 Mertk有 由一项独立研究（Huang等人，自然免疫学，2021）与吞噬吞噬有关 小胶质细胞的丝状A [L及其最终压实到无害致密的核心斑块中。我们在这里提出 一种系统的方法，是了解这种仍然模糊的小胶质细胞介导的认知下降过程。 首先，我们将使用小鼠遗传学来研究trem2顺序参与的要求，然后 通过AXL，随后MERTK可能在小胶质细胞介导的小鼠模型中的认知下降的停滞中 通过行为测试和学习和记忆的电生理评估进行广告。第二，我们会的 将学习和记忆中的这些遗传性上自上毒相关的功能变化与相应的功能变化相关联 通过单核RNA测序评估的小胶质细胞的转录状态。我们的第三个目标是评估 细胞，亚细胞，形态和神经元网络水平脑功能变化，包括AD 神经病理学的标志，例如淀粉样蛋白斑块和tau磷酸化以及小胶质细胞功能 例如吞噬作用和/或斑块屏障形成。我们假设一个Trem2，Axl和Mertk Triad 依次发挥作用，以设计有益的小胶质细胞状态，这反过 这表现为认知能力下降。因此，增强该三合会的功能将限制认知 衰落并保留AD中的大脑健康。我们的研究可能会导致多价参与的发展 小胶质细胞trem2，axl和mertk，用于AD中的新型疗法。