ABCG1 and ABCG4 Suppress gamma-Secretase Activity and Amyloid beta Production

作者：Sano Osamu; Tsujita Maki; Shimizu Yuji; Kato Reiko; Kobayashi Aya; Kioka Noriyuki; Remaley Alan T; Michikawa Makoto; Ueda Kazumitsu; Matsuo Michinori^*

来源：PLos One, 2016, 11(5): e0155400.

DOI：10.1371/journal.pone.0155400

ATP-binding cassette G1 (ABCG1) and ABCG4, expressed in neurons and glia in the central nervous system, mediate cholesterol efflux to lipid acceptors. The relationship between cholesterol level in the central nervous system and Alzheimer's disease has been reported. In this study, we examined the effects of ABCG1 and ABCG4 on amyloid precursor protein (APP) processing, the product of which, amyloid beta (A beta), is involved in the pathogenesis of Alzheimer's disease. Expression of ABCG1 or ABCG4 in human embryonic kidney 293 cells that stably expressed Swedish-type mutant APP increased cellular and cell surface APP levels. Products of cleavage from APP by alpha-secretase and by beta-secretase also increased. The levels of secreted A beta, however, decreased in the presence of ABCG1 and ABCG4, but not ABCG4-KM, a nonfunctional Walker-A lysine mutant. In contrast, secreted A beta levels increased in differentiated SH-SY5Y neuron-like cells in which ABCG1 and ABCG4 were suppressed. Furthermore, A beta 42 peptide in the cerebrospinal fluid from Abcg1 null mice significantly increased compared to the wild type mice. To examine the underlying mechanism, we analyzed the activity and distribution of gamma-secretase. ABCG1 and ABCG4 suppressed gamma-secretase activity and disturbed gamma-secretase localization in the raft domains where gamma-secretase functions. These results suggest that ABCG1 and ABCG4 alter the distribution of -secretase on the plasma membrane, leading to the decreased -secretase activity and suppressed A beta secretion. ABCG1 and ABCG4 may inhibit the development of Alzheimer's disease and can be targets for the treatment of Alzheimer's disease.

• 出版日期2016-5-19