ATP-binding cassette transporter A7 (ABCA7) effects on amyloid processing and relevance to Alzheimer's disease

ATP-binding cassette transporter A7 (ABCA7) is a member of the ABC transporter family associated with phagocytosis. ABCA7 is highly homologous to ABCA1, which act as critical gatekeeper regulating cellular cholesterol efflux to extracellular apolipoprotein acceptors. Transcriptional regulation of ABCA7 is negatively regulated by cell cholesterol, mediated by sterol regulatory element binding protein 2, in the opposite direction to that of ABCA1. Genetic, biochemical and pharmacological evidences indicate that alternations in cholesterol homeostasis increase the risk of Alzheimer's disease (AD). ABCA7 was recently identified as the susceptibility loci by a genome-wide association study (GWAS) which revealed specific AD risk alleles. However, molecular mechanism of ABCA7 pathway under the AD is still unclear. We have therefore undertaken investigations to determine ABCA7 effects on amyloid precursor protein (APP) processing, Aß production and Aß uptake in vitro and/or in vivo. Over-expression of full-length human ABCA7 in HeLa cells was associated with lower Aß production while ABCA7 knockdown resulted in modestly higher Aß production when co-transfected with APP. Similar events appear to occur in vivo shown by the examination of endogenous amyloid processing in an ABCA7 knock-out mouse model. Endogenous murine Aβ expression levels on the ABCA7 ablated background were higher than that in wild-type control mice at early ages. However, this effect was reduced as the mice aged suggesting a compensatory mechanism for APP processing following the loss of ABCA7. The influence of high cholesterol was also investigated, and endogenous murine Aß levels in the ABCA7 knockout mice were significantly elevated in mice on high-fat diets. Wild-type mice on a similar diet also displayed elevated Aß but these were slightly lower than those observed in the ABCA7 knockouts. These results imply that cholesterol affects on Aß processing through not only γ-secretase pathway but also Aß-secretase or potentially APP expression and/or turnover. Taken together, ABCA7 seems to be one of the key molecules linking not only sterol homeostasis but also Alzheimer's disease potentially through APP processing and Aß production.