Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
Nat Immunol. 2023 Mar;24(3):545-557. doi: 10.1038/s41590-022-01403-y. Epub 2023 Jan 19.
The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.
TREM2-DAP12 受体复合物维持小胶质细胞的功能。杂合功能低下的 TREM2 变体削弱了小胶质细胞，加速了晚发性阿尔茨海默病的发生。TREM2 或 TYROBP 编码的 DAP12 同源失活变体导致 Nasu-Hakola 病（NHD），这是一种早发性痴呆症，其特征是脑萎缩、髓鞘丢失和神经胶质增生。NHD 的发病机制尚不清楚。在这里，对 DAP12 缺陷 NHD 个体的大脑标本进行的单细胞 RNA 测序分析揭示了一种独特的小胶质细胞特征，表明 RUNX1、STAT3 和转化生长因子-β信号通路被激活，这些通路介导对损伤的修复反应。该特征与星形胶质细胞中的伤口愈合特征和少突胶质细胞中的髓鞘形成受损相关，而周细胞特征则表明存在血管异常。相反，缺乏 DAP12 信号的小鼠的单细胞特征反映出非常轻微的小胶质细胞缺陷，这些缺陷不能重现 NHD。我们设想，小胶质细胞中的 DAP12 信号减弱了伤口愈合途径，如果不加以控制，这些途径会干扰小胶质细胞的生理功能，从而导致人类的病理。失调的 NHD 小胶质细胞特征的鉴定为重置小胶质细胞信号通路提供了潜在的治疗策略。
