TY - JOUR
T1 - TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4
AU - Gratuze, Maud
AU - Schlachetzki, Johannes C.M.
AU - D'Oliveira Albanus, Ricardo
AU - Jain, Nimansha
AU - Novotny, Brenna
AU - Brase, Logan
AU - Rodriguez, Lea
AU - Mansel, Clayton
AU - Kipnis, Michal
AU - O'Brien, Sydney
AU - Pasillas, Martina P.
AU - Lee, Choonghee
AU - Manis, Melissa
AU - Colonna, Marco
AU - Harari, Oscar
AU - Glass, Christopher K.
AU - Ulrich, Jason D.
AU - Holtzman, David M.
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2023/1/18
Y1 - 2023/1/18
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - ApoE4
KW - TREM2
KW - microgliosis
KW - tau pathology
KW - tau-mediated neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=85146240487&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2022.10.022
DO - 10.1016/j.neuron.2022.10.022
M3 - Article
C2 - 36368315
AN - SCOPUS:85146240487
SN - 0896-6273
VL - 111
SP - 202-219.e7
JO - Neuron
JF - Neuron
IS - 2
ER -