CARD9 attenuates Ab pathology and modifies microglial responses in an Alzheimer's disease mouse model

Although significant progress in recent years has been made in defining key innate immune receptors involved in Alzheimer's disease (AD), our knowledge of the specific intracellular signaling molecules that coordinate immune responses in AD remains poorly defined. In these studies, we have identified a previously undescribed role for the innate immune signaling molecule CARD9 in an amyloid beta (Ab)-mediated mouse model of AD. We specifically demonstrate that CARD9 deletion in the 5xFAD mouse model of AD leads to impaired control of Ab, worsened cognitive decline, and aberrant microglial activation. We further show that pharmacological activation of CARD9 provides a strategy to boost Ab clearance from the hippocampus. Collectively, these findings uncover a previously uncharacterized molecular signaling molecule used by the innate immune system in Ab-mediated neurological disease, and help to establish CARD9 as a novel molecular player that can be targeted in AD. Comparison of 5xFAD microglial response with or without Card9 function. 4 replicates per group of non disease (WT), Card9-deficient, 5xFAD, and 5xFAD Card9 deficient尽管近年来在明确阿尔茨海默病（Alzheimer's Disease, AD）相关的关键天然免疫受体方面已取得显著进展，但目前我们对协调阿尔茨海默病免疫应答的特异性细胞内信号分子的认知仍较为匮乏。本研究揭示了天然免疫信号分子CARD9在β淀粉样蛋白（Amyloid Beta, Aβ）介导的阿尔茨海默病小鼠模型中此前未被报道的功能。研究证实，在阿尔茨海默病5xFAD小鼠模型中敲除CARD9，会导致β淀粉样蛋白调控能力受损、认知衰退加剧以及小胶质细胞异常活化。本研究进一步证明，对CARD9进行药理学激活可作为提升海马体β淀粉样蛋白清除率的有效策略。综上，本研究发现了天然免疫系统在β淀粉样蛋白介导的神经疾病中所利用的一种此前未被鉴定的分子信号分子，并确立了CARD9作为阿尔茨海默病潜在治疗靶点的新型分子角色。本实验对比了有无Card9功能的5xFAD小鼠小胶质细胞应答差异，实验分为野生型（Wild Type, WT）、Card9敲除型、5xFAD模型组以及5xFAD联合Card9敲除型四组，每组设置4个生物学重复。