@article{ad4b52d95d474890b3585a793459459a,
title = "Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia",
abstract = "The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease and directly influences tauopathy and tau-mediated neurodegeneration. ApoE4 has strong deleterious effects on both parameters. In the brain, apoE is produced and secreted primarily by astrocytes and by activated microglia. The cell-specific role of each form of apoE in the setting of neurodegeneration has not been determined. We generated P301S Tau/Aldh1l1-CreERT2/apoE3flox/flox or Tau/Aldh1l1-CreERT2/apoE4flox/flox mice. At 5.5 months of age, after the onset of tau pathology, we administered tamoxifen or vehicle and compared mice at 9.5 months of age. Removing astrocytic APOE4 markedly reduced tau-mediated neurodegeneration and decreased phosphorylated tau (pTau) pathology. Single-nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types, with astrocytic APOE4 removal decreasing disease-associated gene signatures in neurons, oligodendrocytes, astrocytes, and microglia. Removal of astrocytic APOE4 decreased tau-induced synaptic loss and microglial phagocytosis of synaptic elements, suggesting a key role for astrocytic apoE in synaptic degeneration.",
keywords = "APOE, astrocyte, microglia, neurodegeneration, tau",
author = "Chao Wang and Monica Xiong and Maud Gratuze and Xin Bao and Yang Shi and Andhey, {Prabhakar Sairam} and Melissa Manis and Caitlin Schroeder and Zhuoran Yin and Charlotte Madore and Oleg Butovsky and Maxim Artyomov and Ulrich, {Jason D.} and Holtzman, {David M.}",
note = "Funding Information: This study was supported by the Cure Alzheimer's Fund (to D.M.H. and O.B.); the JPB Foundation; National Institutes of Health (NIH) grants NS090934 (to D.M.H.), AG047644 (to D.M.H.), NS088137 (to O.B.), AG054672 (to O.B.), and AG051812 (to O.B.); and the Farrell Family gift to support AD research (to D.M.H.). Scanning of immunohistochemistry was performed on the NanoZoomer digital pathology system courtesy of the Hope Center Alafi Neuroimaging Laboratory. Confocal data were partially generated on a Zeiss LSM 880 Airyscan confocal microscope, which was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director, under grant OD021629 and in part with support from the Washington University Center for Cellular Imaging (WUCCI), supported by Washington University School of Medicine, The Children's Discovery Institute of Washington University and St. Louis Children's Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the Foundation for Barnes-Jewish Hospital (3770 and 4642). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The center is partially supported by NCI Cancer Center support grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant UL1TR002345 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. We thank Drs. Eric Reiman, Geidy Serrano, and Thomas Beach for human brain tissue. C.W. J.D.U. and D.M.H. conceived the study. C.W. J.D.U. and D.M.H. designed the study. C.W. performed most experiments and analyzed the data, assisted by M.X. M.G. X.B. Y.S. P.S.A. M.M. M.A. C.M. Z.Y. O.B. and J.D.U. C.W. and M.X. performed Aqp4 studies. C.W. and M.G. performed microglial engulfment studies. Y.S. isolated microglia from adult mouse brains. J.D.U. processed the snRNA-seq raw data and generated the snRNA-seq-related plots for the figures. D.M.H. and J.D.U. supervised the research. C.W. 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. co-founded and is on the scientific advisory board of C2N Diagnostics. C2N Diagnostics has licensed certain anti-tau antibodies to AbbVie for therapeutic development. D.M.H. is on the scientific advisory board of Denali and consults for Genentech, Merck, and Cajal Neuroscience. All other authors declare no competing interests. Funding Information: This study was supported by the Cure Alzheimer's Fund (to D.M.H. and O.B.); the JPB Foundation ; National Institutes of Health (NIH) grants NS090934 (to D.M.H.), AG047644 (to D.M.H.), NS088137 (to O.B.), AG054672 (to O.B.), and AG051812 (to O.B.); and the Farrell Family gift to support AD research (to D.M.H.). Scanning of immunohistochemistry was performed on the NanoZoomer digital pathology system courtesy of the Hope Center Alafi Neuroimaging Laboratory. Confocal data were partially generated on a Zeiss LSM 880 Airyscan confocal microscope, which was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director, under grant OD021629 and in part with support from the Washington University Center for Cellular Imaging (WUCCI), supported by Washington University School of Medicine , The Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital ( CDI-CORE-2015-505 and CDI-CORE-2019-813 ), and the Foundation for Barnes-Jewish Hospital ( 3770 and 4642 ). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The center is partially supported by NCI Cancer Center support grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant UL1TR002345 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research . This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. We thank Drs. Eric Reiman, Geidy Serrano, and Thomas Beach for human brain tissue. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = may,
day = "19",
doi = "10.1016/j.neuron.2021.03.024",
language = "English",
volume = "109",
pages = "1657--1674.e7",
journal = "Neuron",
issn = "0896-6273",
number = "10",
}