Wild Type and Tangier Disease ABCA1 Mutants Modulate Cellular Amyloid-beta Production Independent of Cholesterol Efflux Activity

Cerebral amyloid-beta (A beta) deposition is a critical feature of Alzheimer's disease. A beta is derived from the amyloid-beta protein precursor (A beta PP) via two sequential cleavages that are mediated by beta-secretase and the gamma-secretase complex. Such amyloidogenic A beta PP processing occurs in lipid raft microdomains of cell membranes and it is thought that modulating the distribution of lipids in rafts may regulate A beta PP processing and A beta production. Certain ATP-binding cassette (ABC) transporters regulate lipid transport across cell membranes and, as recent studies reveal, within membrane microdomains. ABCA1 also regulates A beta metabolism in the brain although its direct impact on A beta PP remains an open question. Here we assessed the capacity of three ABCA1 mutants (that do not promote lipid efflux) to modulate A beta PP processing. Unexpectedly, these non-functional mutants also reduced A beta production similar to wild type ABCA1. ABCA1 expression did not alter A beta PP localization in lipid rafts, and co-immunoprecipitation experiments indicated ABCA1 and A beta PP physically interact. These data suggest that ABCA1 may regulate A beta PP processing independent of its impact on membrane lipid homeostasis.