4.8 Article

Article TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4

Journal

NEURON
Volume 111, Issue 2, Pages 202-+

Publisher

CELL PRESS
DOI: 10.1016/j.neuron.2022.10.022

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In addition to tau and Ab pathologies, inflammation and variants in APOE and TREM2 play important roles in Alzheimer's disease (AD). This study explores the relationship between microgliosis and tau-mediated neurodegeneration in the presence of ApoE4. Surprisingly, the knockout of TREM2 exacerbates neurodegeneration and tau pathology, suggesting that tau pathology-dependent microgliosis facilitates neurodegeneration in the presence of ApoE4.
In addition to tau and Ab pathologies, inflammation plays an important role in Alzheimer's disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4.

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