ABCA5 Regulates Amyloid-β Peptide Production and is Associated with Alzheimer's Disease Neuropathology

Brain cholesterol homeostasis is regulated by a group of proteins called ATP-binding cassette subfamily A (ABCA) transporters. Certain ABCA transporters regulate amyloid-beta protein precursor (A beta PP) processing to generate amyloid-beta peptides (A beta) and are associated with an increased risk for late-onset Alzheimer's disease (AD). ABCA5 is a little-known member of the ABCA subfamily with no known function. In this study we undertook a comprehensive analysis of ABCA5 expression in the human and mouse brains. We explored the potential role of ABCA5 in A beta PP processing associated with AD pathology. ABCA5 was differentially expressed in multiple regions of both human and mouse brains. It was strongly expressed in neurons with only weak expression in microglia, astrocytes, and oligodendrocytes. ABCA5 was able to stimulate cholesterol efflux in neurons. ABCA5 expression was specifically elevated in the hippocampus of AD brains. Using two in vitro cell systems we demonstrated that ABCA5 reduces A beta production, both A beta(40) and A beta(42), without altering A beta PP mRNA and protein levels, indicating that the decrease in the A beta levels was due to changes in A beta PP processing and not A beta PP expression. This report represents the first extensive expression and functional study of ABCA5 in the human brain and our data suggest a plausible function of ABCA5 in the brain as a cholesterol transporter associated with a A beta generation, information that may offer a potential new target for controlling A beta levels in the brain.