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


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.

SUBMITTER: Liu CC 

PROVIDER: S-EPMC8824726 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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<i>APOE3</i>-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia.

Liu Chia-Chen CC   Murray Melissa E ME   Li Xia X   Zhao Na N   Wang Na N   Heckman Michael G MG   Shue Francis F   Martens Yuka Y   Li Yonghe Y   Raulin Ana-Caroline AC   Rosenberg Cassandra L CL   Doss Sydney V SV   Zhao Jing J   Wren Melissa C MC   Jia Lin L   Ren Yingxue Y   Ikezu Tadafumi C TC   Lu Wenyan W   Fu Yuan Y   Caulfield Thomas T   Trottier Zachary A ZA   Knight Joshua J   Chen Yixing Y   Linares Cynthia C   Wang Xue X   Kurti Aishe A   Asmann Yan W YW   Wszolek Zbigniew K ZK   Smith Glenn E GE   Vemuri Prashanthi P   Kantarci Kejal K   Knopman David S DS   Lowe Val J VJ   Jack Clifford R CR   Parisi Joseph E JE   Ferman Tanis J TJ   Boeve Bradley F BF   Graff-Radford Neill R NR   Petersen Ronald C RC   Younkin Steven G SG   Fryer John D JD   Wang Hu H   Han Xianlin X   Frieden Carl C   Dickson Dennis W DW   Ross Owen A OA   Bu Guojun G  

Science translational medicine 20210929 613


Apolipoprotein E (<i>APOE</i>) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an <i>APOE3</i> variant (<i>APOE</i>3-V236E), named <i>APOE3</i>-Jacksonville (<i>APOE3</i>-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 as  ...[more]

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