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

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. Rosenberg, Sydney V. Doss, Jing Zhao, Melissa C. Wren, Lin Jia, Yingxue Ren, Tadafumi C. Ikezu, Wenyan Lu, Yuan Fu, Thomas CaulfieldZachary 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-Radford, Ronald C. Petersen, Steven G. Younkin, John D. Fryer, Hu Wang, Xianlin Han, Carl Frieden, Dennis W. Dickson, Owen A. Ross, Guojun Bu

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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 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.

Original languageEnglish
Article numbereabc9375
JournalScience translational medicine
Issue number613
StatePublished - Sep 29 2021


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