Department of Neurosciences, The Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
Kent State University, School of Biomedical Sciences, Kent, OH, USA.
Mol Neurodegener. 2017 Oct 16;12(1):74. doi: 10.1186/s13024-017-0216-6.
Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular.
Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways.
Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aβ and tau pathologies.
髓系细胞触发受体-2（TREM2）的遗传变异可增加迟发性阿尔茨海默病（LOAD）和其他神经退行性疾病的发病风险。最近的研究深入了解了 TREM2 在调节 AD 中观察到的细胞外β-淀粉样蛋白（Aβ）病理、髓样细胞积累和炎症的多方面作用，但对于 TREM2 在调节神经退行性疾病和 AD 中细胞内微管相关蛋白 tau（MAPT；tau）病理的作用知之甚少。
我们报道称，TREM2 缺失会导致tau 病理的过度磷酸化和聚集加速和加剧，在 tau 病的人源化小鼠模型中。TREM2 缺失也会间接导致神经元应激激酶途径的广泛显著失调。
我们的结果表明，小胶质细胞 TREM2 的缺失会导致 tau 病理增加，并伴有激活的神经元应激激酶的广泛增加。这些发现为 TREM2 在调节 Aβ 和 tau 病理中的复杂、多种作用提供了新的见解。
