In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 13, No. 613 ( 2021-09-29)
Abstract:
Apolipoprotein E ( APOE ) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant ( APOE 3-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.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.abc9375
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2021