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

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 t...

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Bibliographic Details
Published in:PloS one 2016-05, Vol.11 (5)
Main Authors: Sano, Osamu, Tsujita, Maki, Shimizu, Yuji, Kato, Reiko, Kobayashi, Aya, Kioka, Noriyuki, Remaley, Alan T, Michikawa, Makoto, Ueda, Kazumitsu, Matsuo, Michinori
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amyloid beta-protein
Binding proteins
Development and progression
Genetic aspects
Physiological aspects
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Summary: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 [gamma]-secretase on the plasma membrane, leading to the decreased [gamma]-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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0155400