Role of ABCA7 in Neural Lipid Metabolism and Its Association with Alzheimer's Disease Neuropathology

Abstract

AbstractBackgroundStrong genetic evidence supports involvement of adenosine triphosphate binding‐cassette transporter subfamily A member 7 (ABCA7) in Alzheimer’s disease (AD) pathogenesis. ABCA7 closely resembles ABCA1, a cholesterol transporter, in structure. However, molecular specificity of ABCA7‐mediated lipid transport and the role of this protein in AD pathophysiology are understood incompletely. We advance the hypothesis that ABCA7 protects against AD development by removing neurodegenerative lipid from the brain.MethodA validated monoclonal antibody was used to measure ABCA7 protein in a cohort of 104 individuals represented by the hippocampus and a different cohort of 119 individuals represented by the parietal cortex. Both cohorts included individuals with Braak stages 0‐V. Changes in ABCA7 level in response to treatment with lipid metabolism modulators were investigated in human microglial C20 and HMC3 and human astrocytic A172 cell lines.ResultTo match for age, the cohorts were subdivided into 63‐78 and 79‐94 age‐at‐death brackets. There was no significant correlation between ABCA7 protein levels and Braak stages. However, individuals with Braak stages II‐V as a group had significantly lower ABCA7 levels than individuals with Braak stages 0/I as a group in the 63‐78 age bracket of both cohorts (Mann‐Whitney p<0.0001 and p=0.003, respectively) and in the 79‐94 bracket of the parietal cortex cohort (p=0.037) but not in the hippocampus cohort (p=0.33). One of the reasons for this difference between the hippocampus and parietal cortex was that ABCA7 levels decreased significantly with age in the Braak stage 0/I group in the hippocampus but not the parietal cortex (p=0.02 vs p=0.77 for ABCA7 levels in the 63‐78 vs 79‐94 age bracket, respectively). An analysis of lipid metabolism using pharmacological modulators revealed that ABCA7 expression in microglial and astrocytic cells does not respond to the intracellular cholesterol level or regulators of intracellular cholesterol metabolism.ConclusionThese results are in line with the hypothesis that ABCA7 prevents AD neuropathogenesis, i.e., loss of ABCA7 protein occurs sharply and early between Braak stages I and II. There also appear to be brain region‐specific changes in ABCA7 expression with age. The neurodegenerative lipid that ABCA7 removes from the brain remains to be identified.