Alzheimer’s disease is a devastating, neurodegenerative disease for which there are a few therapeutics and no cure. Of individuals over the age of 65, African Americans are about twice as likely to develop Alzheimer’s disease (AD) compared to White American counterparts. This disparity has been partially attributed to the presence of high frequency genetic variants of the ABCA7 gene. The ABCA7 gene encodes ATP binding cassette protein, family member A7, an active, membrane transport protein expressed in neurons, microglia, and astrocytes, and is responsible for translocating lipids across the cell membrane and is implicated in the routine clearance of Aβ plaques via macrophage mediated phagocytosis. Considering ABCA7’s role in lipid trafficking and the clearance of Aβ plaques and the location of the mutated residues in identified AD-associated variants, we hypothesize that these variants may alter lipid binding and/or transport through modified interactions with apolipoprotein, thus altering cellular lipid composition and metabolism. To investigate the impact of these ABCA7 genetic variants on cellular lipid environment and metabolism, we transiently expressed wild-type ABCA7 and the variants in HEK293 cells. The cells were then fixed and stained with fluorescent antibodies against ABCA7, apolipoprotein E (ApoE), lipids, and nuclei. Fluorescence confocal microscopy revealed an increased number of lipid droplets and increased ApoE expression in cells transfected with the disease associated variants. In addition, ATP hydrolysis assays suggest that ApoE is able to modulate ABCA7 activity. These results point to a potential interaction between ABCA7 and ApoE in the presence of lipids that may be altered in the case of the AD-associated genetic variants.
Grimsley et al. (Sun,) studied this question.