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 - Funding Information:
This study was supported by the JPB Foundation (D.M.H. and C.K.G.); Cure Alzheimer's Fund (D.M.H.); National Institutes of Health (NIH) grants RF1AG047644 (D.M.H.), RF1NS090934 (D.M.H.), 1RF1 AG061060 (C.K.G. and J.S.), and R01 AG056511 (C.K.G. and J.S.); and the BrightFocus Foundation (M.G. A2020257F). This publication includes data generated at the UC San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a NIH SIG grant (#S10 OD026929). For the human data, this work was possible thanks to the following grants from the NIH: NIA R01AG057777, R56AG067764, U01AD072464, P30AG066444, P01AG026276, R01AG044546, P01AG003991, RF1AG053303, and U01AG072464, and the Chan Zuckerberg Initiative. O.H. is an Archer Foundation Research Scientist. Study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (R.O.S.), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (M.A.P.), R01AG30146 and RF1AG57473 (single nucleus RNA-seq), U01AG32984 (genomic and whole exome sequencing), and U01AG61356 (whole genome sequencing, ROSMAP AMP-AD). Confocal data were generated on a Zeiss LSM 880 Airyscan Confocal Microscope (grant OD021629; WUCCI; CDI-CORE-2015-505; and CDI-CORE-2019-813, 3770, and 4642). The authors specifically thank Travis Tabor and Alexandra Litvinchuk for their helpful advice for the staining of neutral lipids. M.G. J.D.U. and D.M.H. conceived and designed the study. M.G. performed the majority of experiments and analyzed the data, assisted by L.R. C.M. M.K. N.J. and C.L. M.M. measured the plasma NfL concentration. N.J. performed the in vitro BMDMs experiments. M.C. provided mouse models. J.S. S.O.B. and M.P. performed nuclei isolation, FANS, and library preparation. J.S. and C.K.G. analyzed the snRNA-seq data. R.D.A, L.B. and B.N. performed the analysis of human snRNA-seq data. O.H. supervised and interpreted the human snRNA-seq data analysis. D.M.H. and J.D.U. supervised the research. M.G. J.D.U. and D.M.H. wrote the manuscript with comments from all authors. D.M.H. is as an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. and J.D.U. are inventors on a submitted patent on TREM2 antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech (South San Francisco, CA), and Cajal Neuroscience and consults for Alector. D.M.H. is on the advisory board for Neuron. We support inclusive, diverse, and equitable research.
Funding Information:
This study was supported by the JPB Foundation (D.M.H. and C.K.G.); Cure Alzheimer’s Fund (D.M.H.); National Institutes of Health (NIH) grants RF1AG047644 (D.M.H.), RF1NS090934 (D.M.H.), 1RF1 AG061060 (C.K.G. and J.S.), and R01 AG056511 (C.K.G. and J.S.); and the BrightFocus Foundation (M.G., A2020257F ). This publication includes data generated at the UC San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a NIH SIG grant (# S10 OD026929 ). For the human data, this work was possible thanks to the following grants from the NIH: NIA R01AG057777 , R56AG067764 , U01AD072464 , P30AG066444 , P01AG026276 , R01AG044546 , P01AG003991 , RF1AG053303 , and U01AG072464 , and the Chan Zuckerberg Initiative. O.H. is an Archer Foundation Research Scientist. Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (R.O.S.), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (M.A.P.), R01AG30146 and RF1AG57473 (single nucleus RNA-seq), U01AG32984 (genomic and whole exome sequencing), and U01AG61356 (whole genome sequencing, ROSMAP AMP-AD). Confocal data were generated on a Zeiss LSM 880 Airyscan Confocal Microscope (grant OD021629 ; WUCCI ; CDI-CORE-2015-505 ; and CDI-CORE-2019-813 , 3770 , and 4642 ). The authors specifically thank Travis Tabor and Alexandra Litvinchuk for their helpful advice for the staining of neutral lipids.
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 -