期刊
MOLECULAR NEURODEGENERATION
卷 12, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13024-017-0216-6
关键词
TREM2; Tauopathy; Alzheimers disease; Inflammation; Immunity
资金
- BrightFocus Foundation grant
- National Research Service Award [1F31AG050409-01A1]
- Stark Neurosciences Research Institute
- Indiana Clinical and Translational Sciences Institute - National Institutes of Health, National Center for Advancing Translational Sciences [UL1TR001108]
- NIH Multi-Center Program Grant
- Alzheimer's Association, National Institute of Aging [R01 AG023012, RF1 AG051495]
- National Institute of Neurological Disorders and Stroke [R01 NS047804]
- National Eye Institute [R01 EY022358]
- Department of Defense grant [W81XWH-13-MRPRA-CSRA]
- Jane and Lee Seidman Fund
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 beta-amyloid (A beta) 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 A beta and tau pathologies.
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