Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n⁺C4b⁺ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

胶质细胞与阿尔茨海默病 (AD) 的发病机制有关。在骨髓细胞 2 (TREM2) 上表达的小胶质细胞受体触发受体变体会增加 AD 风险，并且疾病相关小胶质细胞 (DAM) 的激活依赖于 AD 小鼠模型中的 TREM2。我们通过单核 RNA 测序调查了 5XFAD 小鼠和人类 AD 中与 AD 病理学和 TREM2 相关的基因表达变化。我们证实了Trem2依赖性 DAM的存在，并确定了以前未发现的 Serpina3n ⁺ C4b ⁺小鼠反应性少突胶质细胞群。有趣的是，在人类 AD 中明显不同的神经胶质表型。小胶质细胞特征让人联想到周围神经损伤中 IRF8 驱动的反应性小胶质细胞。少突胶质细胞特征表明轴突髓鞘形成和对神经元变性的代谢适应受损。星形胶质细胞概况表明与神经元的代谢协调减弱。值得注意的是，小胶质细胞的反应表型在TREM2- R47H 和TREM2 -R62H 携带者中不如在非携带者中明显，表明小鼠和人类 AD 都需要 TREM2，尽管存在明显的物种特异性差异。