@article{6c237491b33346a5a9fb9a16c0a3ff37,
title = "Cholesterol and matrisome pathways dysregulated in astrocytes and microglia",
abstract = "The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.",
keywords = "APOE, Alzheimer, astrocytes, cholesterol, genetic heterogeneity, haplotypes, iPSC disease modeling, inflammation, matrisome, microglia",
author = "Julia TCW and Lu Qian and Pipalia, {Nina H.} and Chao, {Michael J.} and Liang, {Shuang A.} and Yang Shi and Jain, {Bharat R.} and Bertelsen, {Sarah E.} and Manav Kapoor and Edoardo Marcora and Elizabeth Sikora and Andrews, {Elizabeth J.} and Martini, {Alessandra C.} and Karch, {Celeste M.} and Elizabeth Head and Holtzman, {David M.} and Bin Zhang and Minghui Wang and Maxfield, {Frederick R.} and Poon, {Wayne W.} and Goate, {Alison M.}",
note = "Funding Information: This study was funded by NIH NIA K01AG062683 (J.TCW.), New York Stem Cell Foundation (J.TCW. via Drunkenmiller fellowship), NIA U19AG069701 (J.TCW., A.M.G., E.M., C.M.K., and D.M.H.), NIA U01AG058635 (A.M.G), the JPB Foundation (A.M.G. and D.M.H.), NIA P50AG016573 (W.W.P.), Alzheimer{\textquoteright}s Orange County AOC-207373 (W.W.P.), NINDS RF1NS090934 (D.M.H.), NIA RF1AG047644 (D.M.H.), NHLBI R01HL093324 (F.R.M.), Cure Alzheimer's Fund (F.R.M.), NIA U01AG046170 (B.Z.), NIA RF1AG057440 (B.Z.), NIA RF1AG074010 (B.Z.), and NIA RF1AG054014 (B.Z., A.M.G.). We thank the NYSCF, Mount Sinai Stem Cell Core, Washington University in St. Louis Knight ADRC ( P30AG066444 ), and University of California , Irvine ADRC ( P30AG066519 ) for providing fibroblasts and hiPSCs; Jill K. Gregory for image illustration; Melanie Oaks and Seung-Ah Chung at the UCI Genomics High-Throughput Facility for RNAseq ( NCRR 1S10RR025496-01 , NIH OD 1S10OD010794-01 and 1S10OD021718-01 ); Louisa Normington (LCN Bioinformatics) for WGCNA assistance; and Santiago Sole Domenech, Ana Maria Cuervo, and Aurora Scrivo for lysosome and autophagic function discussion. Funding Information: This study was funded by NIH NIA K01AG062683 (J.TCW.), New York Stem Cell Foundation (J.TCW. via Drunkenmiller fellowship), NIA U19AG069701 (J.TCW. A.M.G. E.M. C.M.K. and D.M.H.), NIA U01AG058635 (A.M.G), the JPB Foundation (A.M.G. and D.M.H.), NIA P50AG016573 (W.W.P.), Alzheimer's Orange County AOC-207373 (W.W.P.), NINDS RF1NS090934 (D.M.H.), NIA RF1AG047644 (D.M.H.), NHLBI R01HL093324 (F.R.M.), Cure Alzheimer's Fund (F.R.M.), NIA U01AG046170 (B.Z.), NIA RF1AG057440 (B.Z.), NIA RF1AG074010 (B.Z.), and NIA RF1AG054014 (B.Z. A.M.G.). We thank the NYSCF, Mount Sinai Stem Cell Core, Washington University in St. Louis Knight ADRC (P30AG066444), and University of California, Irvine ADRC (P30AG066519) for providing fibroblasts and hiPSCs; Jill K. Gregory for image illustration; Melanie Oaks and Seung-Ah Chung at the UCI Genomics High-Throughput Facility for RNAseq (NCRR 1S10RR025496-01, NIH OD 1S10OD010794-01 and 1S10OD021718-01); Louisa Normington (LCN Bioinformatics) for WGCNA assistance; and Santiago Sole Domenech, Ana Maria Cuervo, and Aurora Scrivo for lysosome and autophagic function discussion. J.TCW. W.W.P. and A.M.G. conceived and designed the study. J.TCW. and M.J.C. ran genetic analysis. J.TCW. performed most of the experiments and data analysis, assisted by the other authors; J.TCW. L.Q. and S.A.L. differentiated cell types from hiPSCs. J.TCW. advised by M.K. performed genetic analysis. J.TCW. assisted by S.B. performed transcriptomic analysis; J.TCW. M.W. and B.Z. performed human brain transcriptomic analysis; N.H.P. and J.TCW. performed lipid assays. J.TCW. and L.Q. executed in vitro assays. Y.S. prepared mouse glia. E.J.A. executed post-mortem brain tissue staining advised by A.C.M. E.H. J.TCW. and W.W.P. J.TCW. W.W.P. and A.M.G wrote the manuscript. All authors discussed the results and commented on the manuscript. J.TCW. co-founded Asmos Therapeutics, LLC, serves on the scientific advisory board of NeuCyte, Inc, and has consulted for FIND Genomics Inc. CareCureSystems Corporation, TheWell Biosciences Inc. and Aleta Neuroscience, LLC. A.M.G. has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics, and GSK and served on the scientific advisory board at Denali Therapeutics from 2015–2018. D.M.H. co-founded and is on the scientific advisory board of C2 N Diagnostics, LLC (licensed anti-tau antibody to AbbVie) and the scientific advisory board of Denali and consults for Genentech and Idorsia. F.R.M. has consulted for Denali Therapeutics in 2019. W.W.P. is a co-inventor of patent WO/2018/160496 (microglia differentiation). We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as living with a disability. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = jun,
day = "23",
doi = "10.1016/j.cell.2022.05.017",
language = "English",
volume = "185",
pages = "2213--2233.e25",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "13",
}