@article{09eabf68a791431c87ef320325325de1,
title = "APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia",
abstract = "Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer{\textquoteright}s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB.",
author = "Liu, {Chia Chen} and Murray, {Melissa E.} and Xia Li and Na Zhao and Na Wang and Heckman, {Michael G.} and Francis Shue and Yuka Martens and Yonghe Li and Raulin, {Ana Caroline} and Rosenberg, {Cassandra L.} and Doss, {Sydney V.} and Jing Zhao and Wren, {Melissa C.} and Lin Jia and Yingxue Ren and Ikezu, {Tadafumi C.} and Wenyan Lu and Yuan Fu and Thomas Caulfield and Trottier, {Zachary A.} and Joshua Knight and Yixing Chen and Cynthia Linares and Xue Wang and Aishe Kurti and Asmann, {Yan W.} and Wszolek, {Zbigniew K.} and Smith, {Glenn E.} and Prashanthi Vemuri and Kejal Kantarci and Knopman, {David S.} and Lowe, {Val J.} and Jack, {Clifford R.} and Parisi, {Joseph E.} and Ferman, {Tanis J.} and Boeve, {Bradley F.} and Graff-Radford, {Neill R.} and Petersen, {Ronald C.} and Younkin, {Steven G.} and Fryer, {John D.} and Hu Wang and Xianlin Han and Carl Frieden and Dickson, {Dennis W.} and Ross, {Owen A.} and Guojun Bu",
note = "Funding Information: We thank A. Strongosky for collecting blood specimens for the research. We thank A. Koslov for performing the AUC experiments and B. Baban for the preparation and purification of WT APOE4 and APOE4-Jac. We are grateful to M. C. Casey, V. Phillips, and A. Librero at Mayo Clinic Histology Core for the immunohistochemical analyses. We thank H. Li for careful reading of the manuscript. This study was supported by NIH grants R37AG027924, RF1AG046205, RF1AG057181, U19AG069701, and P01NS074969 and a grant from the Cure Alzheimer{\textquoteright}s Fund (to G.B.); an NIH grant R01AG062110, Florida Department of Health Ed and Ethel Moore Alzheimer{\textquoteright}s Disease Research Program (8AZ07), and a grant from Brightfocus (to C.-C.L.); an NIH grant R01AG054449, a grant from the Florida Department of Health Ed and Ethel Moore Alzheimer{\textquoteright}s Disease Research Program (20a22), and support through the foundation by Nelson Family Genomics Research Fund and Gerstner Family Career Development Award (to M.E.M.); and an NIH grant RF1AG061872 (to X.H.). Mayo Clinic Lewy body disease studies are supported by American Parkinson Disease Association (APDA) Information and Referral Center, an APDA Center for Advanced Research, a Lewy Body Dementia Association (LBDA) Research Center of Excellence and a Lewy Body Dementia Center Without Walls (U54 NS110435). The Mayo Clinic Brain Bank and genetics programs are supported by Morris K. Udall Parkinson{\textquoteright}s Disease Research Center of Excellence (NINDS P50 #NS072187); Alzheimer{\textquoteright}s Disease Research Center (NIA P30AG062677); Mayo Clinic Study of Aging (NIA U01AG006786); R01NS078086, R01NS076471, R01AG015866, R01AG11378, and R01AG041851 (to C.R.J.); the Mayo Clinic Center of Individualized Medicine Award for Familial Longevity Sequencing Project; the Mayo Clinic AD and related dementias genetics program; the Elsie and Marvin Dekelboum Family Foundation; The Mayo Clinic Functional Genomics of LBD program, supported by Ted Turner and family; The Little Family Foundation; and the Mangurian Foundation for Lewy body research. Z.K.W. is partially supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, gifts from The Sol Goldman Charitable Trust, the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson{\textquoteright}s Research Foundation. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved;",
year = "2021",
month = sep,
day = "29",
doi = "10.1126/scitranslmed.abc9375",
language = "English (US)",
volume = "13",
journal = "Science translational medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "613",
}