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

项目摘要/摘要 几十年来对阿尔茨海默病(AD)的研究的一个分水岭时刻是发现针对某些特定的 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，并阻止 认知能力下降。用于AD治疗的第一类小胶质分子靶点是TREM2。TREM2表达 在AD大脑中的小胶质细胞中上调，小胶质细胞从动态平衡状态变化到某种已知的状态 如转录组学所定义的损伤相关小胶质细胞(DAM)，而TREM2的丢失阻止了DAM 在加速疾病进展的同时进行过渡。值得注意的是，TREM2的丢失阻止了 另一种小胶质分子--Axl。AXL在大坝介导的阻挠中是否具有关键效应作用 认知能力下降的原因到目前为止还不得而知。我们发现，增加Axl导致了逮捕 阿尔茨海默病小鼠模型的认知能力下降。在这个轴心上有一个潜在的第三个参与者-MERTK。MerTK有 一项独立研究(Huang等人，《自然免疫学》，2021年)与吞噬细胞吞噬有关 丝状A[L]的小胶质细胞及其最终压实成无害的致密核心斑块。在这里，我们建议 一个系统的方法来理解这个仍然模糊的过程，小胶质细胞介导的认知能力下降的停止。 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 AXL和可能随后通过MERTK在小胶质细胞介导的小鼠认知功能减退模型中的作用 AD通过行为学测试和电生理评估学习记忆。第二，我们将 将这些与遗传上位性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 神经病理特征，如淀粉样斑块和tau磷酸化，以及小胶质细胞功能 如吞噬和/或斑块屏障形成。我们假设TREM2、AXL和MERTK三合会 顺序性地调节有益的小胶质细胞状态，进而对抗AD相关的不良影响 这表现为认知能力的下降。因此，扩大这个三和弦的功能会抑制认知 在AD中降低和保护大脑健康。我们的研究可能导致多价结合的发展 小胶质细胞分子TREM2、AXL和MERTK，用于AD的新疗法。

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.