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.

项目总结/摘要 几十年来阿尔茨海默病（AD）研究的一个分水岭是发现，针对某些 小胶质细胞中的分子可以改善这些细胞中迄今未知的功能机制， 认知能力下降用于AD治疗的第一类小胶质细胞分子靶标是TREM 2。trem 2表达 在AD脑中的小胶质细胞中上调，小胶质细胞从稳态变为已知的 如转录组学定义的损伤相关小胶质细胞（DAM），TREM 2的缺失可防止DAM 同时加速疾病进展。值得注意的是，TREM 2的缺失阻止了TREM 2的上调。 另一种小胶质细胞分子- AXL。AXL是否在DAM介导的阻遏中具有关键效应器功能 认知能力下降的可能性迄今为止仍然未知。我们发现增加AXL可以阻止 AD小鼠模型的认知能力下降。在这个轴心中有一个潜在的第三个玩家- MERTK。MERTK已 被一项独立的研究所牵连（Huang等人，Nature Immunology，2021）在吞噬细胞吞噬中 丝状A[1]被小胶质细胞吞噬并最终压缩成无害的致密核心斑块。在这里我们建议 一种系统的方法来理解小胶质细胞介导的认知衰退停滞的这一仍然模糊的过程。 首先，我们将使用小鼠遗传学来研究TREM 2顺序参与的要求，然后 AXL和随后可能的MERTK在小胶质细胞介导的小鼠模型中的认知衰退停滞中的作用 通过行为学测试和电生理学评估AD的学习和记忆。二是 将这些遗传上位相关的学习和记忆功能变化与相应的 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、形态学和神经元网络水平的脑功能变化，包括AD 神经病理学标志，如淀粉样斑块和tau磷酸化，以及小胶质细胞功能 例如吞噬作用和/或噬斑屏障形成。我们假设TREM 2、AXL和MERTK三联体 依次发挥作用，以设计有益的小胶质细胞状态，从而对抗AD相关的不良影响 表现为认知能力下降因此，增强这一三联体的功能将抑制认知 降低并保持AD患者的大脑健康。我们的研究可能会导致多价接合的发展， 小胶质细胞分子TREM 2、AXL和MERTK，用于AD的新疗法。