Abstract
BackgroundGenetic 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.ResultsHere 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.ConclusionsOur 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.
Highlights
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
TREM2 deficiency worsens tau pathology in hTau mice Humanized tau mice lack the endogenous mouse Mapt gene, but instead express the full-length human microtubule associated protein tau (MAPT) gene driven under the endogenous human MAPT promoter [25, 26]. hTau mice develop age-related hyperphosphorylation, aggregation and mislocalization of tau, and exhibit modest behavioral abnormalities with age
To explore the effect of TREM2 deficiency on tau pathology and microglial mediated inflammation, hTau mice were mated to Trem2−/− mice to generate hTau;Trem2+/+ and hTau;Trem2−/− mice [20, 26]
Summary
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. TREM2 coding variants have been associated with increased risk for amyotrophic lateral sclerosis (ALS) and frontotemporal-lobar dementia (FTLD) [17,18,19] Taken together, these data suggest that TREM2 likely plays a critical role in regulating myeloid cell function within the brain, thereby modulating risk for neurodegenerative diseases. These data suggest that TREM2 likely plays a critical role in regulating myeloid cell function within the brain, thereby modulating risk for neurodegenerative diseases Despite this abundance of genetic validation, the pathways linking TREM2 to neurodegenerative disease have yet to be Bemiller et al Molecular Neurodegeneration (2017) 12:74 identified and strategies for therapeutic modulation are not evident
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