Alector LLC, South San Francisco, USA.
Alector LLC, South San Francisco, USA.
Neurobiol Dis. 2020 Sep;143:104962. doi: 10.1016/j.nbd.2020.104962. Epub 2020 Jun 12.
Recent human genetic studies have challenged long standing hypotheses about the chain of events in Alzheimer's disease (AD), as the identification of genetic risk factors in microglial genes supports a causative role for microglia in the disease. Parallel transcriptome and histology studies at the single-cell level revealed a rich palette of microglial states affected by disease status and genetic risk factors. Taken together, those findings support microglia dysfunction as a central mechanism in AD etiology and thus the therapeutic potential of modulating microglial activity for AD treatment. Here we review how human genetic studies discovered microglial AD risk genes, such as TREM2, CD33, MS4A and APOE, and how experimental studies are beginning to decipher the cellular functions of some of these genes. Our review also focuses on recent transcriptomic studies of human microglia from postmortem tissue to critically assess areas of similarity and dissimilarity between human and mouse models currently in use in order to better understand the biology of innate immunity in AD.
最近的人类遗传学研究挑战了阿尔茨海默病（AD）发病机制的长期假说，因为在小胶质细胞基因中发现遗传风险因素支持小胶质细胞在疾病中的因果作用。单细胞水平的平行转录组学和组织学研究揭示了受疾病状态和遗传风险因素影响的丰富小胶质细胞状态。总的来说，这些发现支持小胶质细胞功能障碍是 AD 发病机制的核心机制，因此调节小胶质细胞活性治疗 AD 具有治疗潜力。在这里，我们回顾了人类遗传学研究如何发现 AD 风险基因，如 TREM2、CD33、MS4A 和 APOE，以及实验研究如何开始破译其中一些基因的细胞功能。我们的综述还重点关注了最近对死后组织中人类小胶质细胞的转录组学研究，以批判性地评估当前用于 AD 研究的人类和小鼠模型之间的相似和不同之处，以便更好地理解 AD 中固有免疫的生物学。
