Details

Autor(en) / Beteiligte

• Gratuze, Maud
• Schlachetzki, Johannes C.M.
• D’Oliveira Albanus, Ricardo
• Jain, Nimansha
• Novotny, Brenna
• Brase, Logan
• Rodriguez, Lea
• Mansel, Clayton
• Kipnis, Michal
• O’Brien, Sydney
• Pasillas, Martina P.
• Lee, Choonghee
• Manis, Melissa
• Colonna, Marco
• Harari, Oscar
• Glass, Christopher K.
• Ulrich, Jason D.
• Holtzman, David M.

Titel

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

Ist Teil von

• Neuron (Cambridge, Mass.), 2023-01, Vol.111 (2), p.202-219.e7

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• In addition to tau and Aβ 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. •TREM2 deletion does not reduce tau-linked neurodegeneration in the presence of ApoE4•TREM2 deletion does not protect against tau pathology in the presence of ApoE4•ApoE4 and tau pathology induce TREM2-independent lysosomal burden in microglia•ApoE4 and tau-associated microgliosis exhibit TREM2-independent lipid accumulation Gratuze et al. demonstrate that TREM2 deletion does not protect against tau pathology and tau-mediated neurodegeneration in the presence of ApoE4. Despite decreasing TREM2-dependent microgliosis, a TREM2-independent microgliosis persists in the presence of ApoE4 and tau pathology that exhibits high microglial lysosomal burden and lipid accumulation.