APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia

• DOI: 10.1126/scitranslmed.abc9375
• Publication Date: 2021-09-29T18:14:01Z
• Authors: Chia-Chen Liu; Melissa E. Murray; Xia Li; Na Zhao; Na Wang; Michael G. Heckman; Francis Shue; Yuka Martens; Yonghe Li; Ana-Caroline Raulin; Cassandra L. Rose...; Sydney V. Doss; Jing Zhao; Melissa C. Wren; Lin Jia; Yingxue Ren; Tadafumi C. Ikezu; Wenyan Lu; Yuan Fu; Thomas Caulfield; Zachary A. Trottier; Joshua Knight; Yixing Chen; Cynthia Linares; Xue Wang; Aishe Kurti; Yan W. Asmann; Zbigniew K. Wszolek; Glenn E. Smith; Prashanthi Vemuri; Kejal Kantarci; David S. Knopman; Val J. Lowe; Clifford R. Jack; Joseph E. Parisi; Tanis J. Ferman; Bradley F. Boeve; Neill R. Graff-Ra...; Ronald C. Petersen; Steven G. Younkin; John D. Fryer; Hu Wang; Xianlin Han; Carl Frieden; Dennis W. Dickson; Owen A. Ross; Guojun Bu
• Keywords: Apolipoprotein E

Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer’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 dementia Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation enhances its lipidation in human brains, as well cellular biochemical assays. Compared APOE3, expression of astrocytes increases several classes lipids including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, sulfatide, critical synaptic functions. Mice expressing amyloid pathology, plaque-associated immune responses, neuritic dystrophy. The V236E substitution is also sufficient reduce APOE4, whose gene allele a major factor DLB. These findings suggest that targeting might be effective strategy treating subgroup individuals