Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Neurology, Union Hospital, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian 350001, China.
Neuron. 2018 Mar 7;97(5):1023-1031.e7. doi: 10.1016/j.neuron.2018.01.031.
Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer's disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to β-amyloid (Aβ) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Aβ binding. TREM2 deficiency impairs Aβ degradation in primary microglial culture and mouse brain. Aβ-induced microglial depolarization, K inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by Aβ, regulating downstream phosphorylation of SYK and GSK3β. Our data demonstrate TREM2 as a microglial Aβ receptor transducing physiological and AD-related pathological effects associated with Aβ.
触发受体表达在髓样细胞 2（TREM2）上的突变与阿尔茨海默病（AD）风险增加有关。TREM2 的神经生物学功能及其病理生理学配体仍不清楚。在这里，我们发现 TREM2 以纳摩尔亲和力直接与β-淀粉样蛋白（Aβ）寡聚体结合，而与 AD 相关的 TREM2 突变会降低 Aβ 的结合。TREM2 缺乏会损害原代小胶质细胞培养物和小鼠大脑中的 Aβ 降解。Aβ 诱导的小胶质细胞去极化、内向 K 电流诱导、细胞因子表达和分泌、迁移、增殖、凋亡以及形态变化依赖于 TREM2。此外，Aβ 增强了 TREM2 与其信号适配器 DAP12 的相互作用，调节下游 SYK 和 GSK3β 的磷酸化。我们的数据表明，TREM2 作为小胶质细胞 Aβ 受体，可传递与 Aβ 相关的生理和 AD 相关的病理效应。
