BPS2026 – Elucidating the interaction of apolipoproteins with ABCA7 in neurodegenerative diseases

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that accounts for 60%–80% of dementia cases, placing a significant burden on patients and their caregivers. Interestingly, genetic variations in regions that encode apolipoproteins are associated with AD, suggesting an involvement in its pathophysiology. Moreover, apolipoprotein E (ε4) variant (ApoE4) is associated with an increased prevalence of AD and apolipoprotein A1 (ApoA1) is implicated in neurodegeneration. Importantly, both apolipoproteins appear to interact with ATP bindingcassette protein, member A7 (ABCA7), a lipid transporter also implicated in AD. Previous studies have reported that ABCA7 can transfer phospholipids across the cell membrane to ApoE and ApoA1 and that ABCA7 ATPase activity is enhanced in the presence of ApoE, but our understanding of how apolipoproteins impact ABCA7 function is limited. Thus, we are using structural and cellular studies to investigate how apolipoproteins interact with ABCA7 in both wild-type and disease-associated variants of ABCA7. Our preliminary studies suggest that AD-associated variants have a modified ability of apolipoprotein to impact ATPase activity and appear to impact ApoE expression levels. For instance, in the case of one higher conferred risk variant, we measured a higher level of ApoE expression compared to wild type. We also see changes in lipid metabolism in these variants and want to know if apolipoproteins play a role in these changes, as we hypothesize that the ABCA7 variants may impact lipid metabolism through altered interactions with apolipoproteins. My project is focused on expressing and purifying ApoE4 and ApoA1 to determine how each interacts with ABCA7 and how their interaction changes in the context of these variants using a combination of structural and functional studies. Understanding the importance of ApoE4 and ApoA1 and their interaction with ABCA7 will allow for a better understanding of AD pathogenesis.