| Literature DB >> 34586832 |
Chia-Chen Liu1, Melissa E Murray1, Xia Li1, Na Zhao1, Na Wang1, Michael G Heckman2, Francis Shue1, Yuka Martens1, Yonghe Li1, Ana-Caroline Raulin1, Cassandra L Rosenberg1, Sydney V Doss1, Jing Zhao1, Melissa C Wren1, Lin Jia1, Yingxue Ren2, Tadafumi C Ikezu1, Wenyan Lu1, Yuan Fu1, Thomas Caulfield1, Zachary A Trottier1, Joshua Knight1, Yixing Chen1, Cynthia Linares1, Xue Wang2, Aishe Kurti1, Yan W Asmann2, Zbigniew K Wszolek3, Glenn E Smith4, Prashanthi Vemuri5, Kejal Kantarci5, David S Knopman6, Val J Lowe5, Clifford R Jack5, Joseph E Parisi6,7, Tanis J Ferman8, Bradley F Boeve6, Neill R Graff-Radford3, Ronald C Petersen6, Steven G Younkin1, John D Fryer9, Hu Wang10, Xianlin Han10,11, Carl Frieden12, Dennis W Dickson1, Owen A Ross1,13, Guojun Bu1.
Abstract
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.Entities:
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Year: 2021 PMID： 34586832 PMCID： PMC8824726 DOI： 10.1126/scitranslmed.abc9375
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 19.319