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- W2896866653 abstract "ApoE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) risk. ABCA1 lipidates ApoE to form ApoE HDL particles. In AD animal models, ApoE4 is hypolipidated. Overexpressing ABCA1 or removing poorly lipidated ApoE4 from the brain prevents brain amyloid accumulation. The goal of this study is to understand the mechanisms of hypolipidated ApoE4 in the brain. We used cell cultures, human apoE4 (hApoE4) targeted replacement mice, and cerebrospinal fluid from humans to study ABCA1-ApoE4 interactions. Treatment of ABCA1 expressing cells with recombinant ApoE4 increased the percentage of ApoE4 and ABCA1 in aggregates and decreased ABCA1 expression and activity in vitro by favoring ABCA1 trafficking into late endosomes destined for lysosomal degradation. In vivo, hippocampal homogenates from 4 months-old male and female hApoE4 mice had significantly more aggregated ApoE and ABCA1 proteins compared with hippocampal homogenates from hApoE3 mice. ApoE – ABCA1 aggregation was associated with hypolipidated ApoE4. Treatment with the ABCA1 agonist CS6253 in vivo and in vitro decreased ApoE4 hypolipidation and the percentage of aggregated ABCA-1 and ApoE4 particles. Concomitantly, treatment with CS6253 reversed AD phenotype in hApoE4 mice by lowering intraneuronal Aβ and P-tau, enhancing glutaminergic, presynaptic-vesicle proteins VGlut1 and VGAT, and reversing cognitive decline assessed by Morris-water-test and novel-object-recognition (all p<0.05). In humans, CSF ApoE was resolved in four distinct bands by electrophoresis α0 (>669 KDa), α1 (600 KDa), α2 (440 KDa) and α3 (232-140 KDa, hypolipidated). Amount of total ApoE present in α0 size was reduced in ε4/ε4 vs ε3/ε3 individuals (3.208 % (SD 0.6156; n=3) vs 8.904 (SD 0.6156 %; n=29), p<0.05), whereas total ApoE in α2 size (hypolipidated) was increased in ε4/ε4 vs ε3/ε3 individuals (60.68 % (SD 8.207; n=3) vs 37.34 % (SD 16.80; n=31), p<0.05). This shift to smaller apoE particles was associated with decreased CSF ABCA-1 activity in ε4/ε4 carriers. Increased aggregation of ApoE4 particles associate with ABCA1 aggregation and lysosomal degradation. Enhancing brain ABCA1 activity decreases ApoE4 hypolipidation and aggregation and reverses AD phenotype in hApoE4 mice. Enhancing brain ABCA1 activity holds promise in the prevention of ApoE4-driven AD." @default.
- W2896866653 created "2018-10-26" @default.
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- W2896866653 date "2018-07-01" @default.
- W2896866653 modified "2023-10-16" @default.
- W2896866653 title "P4‐242: APOE4 AGGREGATION AND HYPOLIPIDATION IS IMPLICATED IN ALZHEIMER'S DISEASE PATHOLOGY IN CELLULAR, ANIMAL AND HUMAN STUDIES" @default.
- W2896866653 doi "https://doi.org/10.1016/j.jalz.2018.07.063" @default.
- W2896866653 hasPublicationYear "2018" @default.
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