TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy

Molecular Neurodegeneration

Richard M. Ransohoff¹  Kevin Allan²  Samuel D. Crish³  Gina Wilson³  Guixiang Xu⁴  Bruce T. Lamb⁴  Shane V. Formica⁴  Olga N. Kokiko-Cochran⁴  Shane M. Bemiller⁴  Gary E. Landreth⁵  Tyler J. McCray⁵  Cristian A. Lasagna-Reeves⁵ 

[1]Biogen IDEC

[2]Department of Neurosciences, Case Western Reserve University

[3]Department of Neurosciences, Northeastern Ohio Medical University

[4]Department of Neurosciences, The Cleveland Clinic Lerner Research Institute

[5]Indiana University School of Medicine Stark Neuroscience Research Institute

关键词: TREM2;    Tauopathy;    Alzheimers disease;    Inflammation;    Immunity;   

DOI  :  10.1186/s13024-017-0216-6

来源: DOAJ

【 摘 要 】

Abstract Background 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. Results 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. Conclusions 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.

【 授权许可】

Unknown