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.

项目概要/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为止未知的功能机制，并阻止 认知能力下降。 AD 治疗的第一个小胶质细胞分子靶标是 TREM2。 TREM2表达 AD 大脑中小胶质细胞的表达上调，小胶质细胞从稳态转变为已知状态 作为转录组学定义的损伤相关小胶质细胞 (DAM)，TREM2 的缺失会阻止 DAM 转变，同时加速疾病进展。值得注意的是，TREM2 的缺失阻止了 另一种小胶质细胞分子——AXL。 AXL 是否在 DAM 介导的阻滞中具有关键效应功能 迄今为止，认知能力下降的原因仍然未知。我们发现增强 AXL 会导致逮捕 AD 小鼠模型中认知能力下降的研究。这个轴上还有一个潜在的第三个参与者——MERTK。 MERTK 有 一项独立研究（Huang 等人，Nature Immunology，2021）暗示吞噬细胞吞噬 小胶质细胞对丝状A[l的作用及其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阻止这一仍然模糊的过程。 首先，我们将利用小鼠遗传学来研究TREM2顺序参与的要求，然后 通过 AXL 和可能随后通过 MERTK 在小胶质细胞介导的小鼠模型中阻止认知能力下降 AD通过行为测试和电生理学评估学习和记忆。其次，我们将 将这些与学习和记忆中的遗传上位相关的功能变化与相应的 通过单核 RNA 测序评估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的脑功能变化，包括 AD 神经病理学标志，例如淀粉样斑块和 tau 磷酸化，以及小胶质细胞功能 例如吞噬作用和/或斑块屏障形成。我们假设 TREM2、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，增强这个三联体的功能会抑制认知 减少 AD 患者的大脑健康并保持其​​健康。我们的研究可能会导致多价参与的发展 小胶质细胞分子 TREM2、AXL 和 MERTK，用于 AD 的新疗法。