美国洛克菲勒大学Sohail F. Tavazoie等研究人员合作发现，衰竭样小胶质细胞群在老年和APOE4基因型阿尔茨海默氏症患者大脑中聚集。2023年12月29日，《免疫》杂志在线发表了这项成果。

研究人员表示，晚期阿尔茨海默病（AD）的主要风险因素是高龄和APOE4基因变异。

为了研究这些因素如何改变神经免疫功能，研究人员在携带三种常见人类APOE等位基因的AD模型小鼠中绘制了大脑免疫细胞的综合纵向单细胞图谱。转录组和染色质可及性分析确定了一个反应性小胶质细胞群体，该群体同时表达炎症信号和细胞内在压力标记物，其频率随年龄和APOE4负荷的增加而增加。利用多重空间转录组学，研究人员在人类AD患者的大脑（包括皮层组织）中检测到了类似的群体。

研究人员将这一群体命名为终末炎性小胶质细胞（TIM），它在阿杜那单抗治疗期间表现出淀粉样蛋白-β清除缺陷和细胞间通讯改变。TIM可能代表了AD环境中炎症性小胶质细胞的一种衰竭样状态，这种状态导致了APOE4携带者和老年人的AD风险和病理变化，从而为AD提供了一个潜在的治疗靶点。

附：英文原文

Title: An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains

Author: Alon Millet, Jose Henrique Ledo, Sohail F. Tavazoie

Issue&Volume: 2023-12-29

Abstract: The dominant risk factors for late-onset Alzheimer’s disease (AD) are advanced ageand the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generatedan integrative, longitudinal single-cell atlas of brain immune cells in AD model micebearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactivemicroglial population defined by the concomitant expression of inflammatory signalsand cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients,including in the cortical tissue, using multiplexed spatial transcriptomics. Thispopulation, which we designate as terminally inflammatory microglia (TIM), exhibiteddefects in amyloid-β clearance and altered cell-cell communication during aducanumabtreatment. TIM may represent an exhausted-like state for inflammatory microglia inthe AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD.

DOI: 10.1016/j.immuni.2023.12.001

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00532-0