Plaque-induced transcriptional reprogramming of microglia towards lymphoid receptor expression protects against Alzheimer’s disease. [RNA-seq]

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD). The microglial response to amyloid plaques can be either neuroprotective or neurotoxic. Here we show that the protective function of microglia is associated with and functionally linked to a transcriptional shift toward lymphoid gene expression. Microglial contact with the plaques induces downregulation of PU.1, a lineage-specifying transcription factor. PU.1 downregulation plays a key role in mitigating the severity of AD, as evidenced by a reduction in neurotoxic microglia activation, preservation of neuronal connections, maintenance of cognitive function, and increased survival in mice with genetically reduced PU.1 expression in microglia. The neuroprotective effect of PU.1 downregulation is linked to the de-repression of lymphoid-specific proteins, particularly CD28—a surface protein critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed exclusively in a small subset of plaque-associated PU.1low microglia, promotes an inflammatory microglial state and associated increase in amyloid plaque load. Our findings suggest that PU.1low lymphoid/CD28-expressing microglia that emerge in response to AD pathology exert a suppressive, anti-inflammatory effect during AD. This novel role of CD28 -and potentially other lymphoid co-stimulatory or co-inhibitory receptor proteins- in governing microglia responses in AD points to possible new immunotherapy approaches for AD treatment. Microglial RNAs were isolated from human HPSC-induced microglia (iMgls)

小胶质细胞（microglia）作为大脑的固有免疫细胞，在阿尔茨海默病（AD）的病程进展中发挥决定性作用。小胶质细胞对淀粉样斑块（amyloid plaques）的应答可表现为神经保护或神经毒性两种效应。本研究证实，小胶质细胞的保护性功能与向淋巴样基因表达的转录偏移相关，且存在功能上的关联。小胶质细胞与斑块的接触会诱导谱系特异性转录因子PU.1（PU.1）的表达下调。PU.1表达下调在缓解AD病情严重程度中发挥关键作用，该结论可通过以下现象得到验证：小胶质细胞中PU.1表达经遗传修饰下调的小鼠，其神经毒性小胶质细胞活化程度降低、神经元连接得以保留、认知功能维持稳定，且生存率显著提升。PU.1表达下调的神经保护效应与淋巴样特异性蛋白的去抑制（de-repression）密切相关，尤其是CD28（CD28）——一种对T细胞活化至关重要的表面蛋白。仅在少量与斑块相关的PU.1低表达（PU.1low）小胶质细胞中表达的CD28，其小胶质细胞特异性缺失会促进促炎性小胶质细胞状态，并伴随淀粉样斑块负荷的增加。本研究结果表明，因AD病理变化而产生的PU.1低表达、表达淋巴样/CD28的小胶质细胞，在AD进程中发挥抑制性的抗炎效应。CD28以及潜在的其他淋巴样共刺激或共抑制受体蛋白（co-stimulatory or co-inhibitory receptor proteins）在调控AD中小胶质细胞应答方面的这一新功能，为AD治疗提供了潜在的新型免疫治疗策略。研究中所用的小胶质细胞RNA均分离自人类HPSC诱导的小胶质细胞（iMgls）。