ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production

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

doi:10.1371/journal.pone.0155400

ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production

PLoS One. 2016 May 19;11(5):e0155400. doi: 10.1371/journal.pone.0155400. eCollection 2016.

Authors

Osamu Sano¹, Maki Tsujita², Yuji Shimizu¹, Reiko Kato¹, Aya Kobayashi¹, Noriyuki Kioka¹, Alan T Remaley³, Makoto Michikawa², Kazumitsu Ueda^{1

4}, Michinori Matsuo^{4

5}

Affiliations

¹ Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Kyoto University Graduate School of Agriculture, Kyoto, 606-8502, Japan.
² Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan.
³ Lipoprotein Metabolism Section, NHLBI, National Institutes of Health, Bethesda, MD, 20892-1508, United States of America.
⁴ iCeMS, Kyoto University, Kyoto, 606-8502, Japan.
⁵ Department of Food and Nutrition, Faculty of Home Economics, Kyoto Women's University, Kyoto, 605-8501, Japan.

Abstract

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 β (Aβ), 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 α-secretase and by β-secretase also increased. The levels of secreted Aβ, however, decreased in the presence of ABCG1 and ABCG4, but not ABCG4-KM, a nonfunctional Walker-A lysine mutant. In contrast, secreted Aβ levels increased in differentiated SH-SY5Y neuron-like cells in which ABCG1 and ABCG4 were suppressed. Furthermore, Aβ42 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 γ-secretase. ABCG1 and ABCG4 suppressed γ-secretase activity and disturbed γ-secretase localization in the raft domains where γ-secretase functions. These results suggest that ABCG1 and ABCG4 alter the distribution of γ-secretase on the plasma membrane, leading to the decreased γ-secretase activity and suppressed Aβ secretion. ABCG1 and ABCG4 may inhibit the development of Alzheimer's disease and can be targets for the treatment of Alzheimer's disease.

MeSH terms

ATP Binding Cassette Transporter, Subfamily G / genetics
ATP Binding Cassette Transporter, Subfamily G / metabolism*
ATP Binding Cassette Transporter, Subfamily G, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily G, Member 1 / metabolism*
Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Peptides / biosynthesis*
Animals
Caveolin 1 / metabolism
Cell Line, Tumor
Cell Membrane / metabolism
Gene Silencing
HEK293 Cells
Humans
Lysine
Membrane Glycoproteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
RNA Interference

Substances

ABCG1 protein, human
ABCG4 protein, human
ATP Binding Cassette Transporter, Subfamily G
ATP Binding Cassette Transporter, Subfamily G, Member 1
Amyloid beta-Peptides
CAV1 protein, human
Caveolin 1
Membrane Glycoproteins
nicastrin protein
Amyloid Precursor Protein Secretases
Lysine

Grants and funding

This work was supported by a Grant-in-aid for Scientific Research for Young Scientists (A) (JSPS KAKENHI Grant Number 21688007), by a Grant-in-aid for Scientific Research (S) (JSPS KAKENHI Grant Number 25221203), by a Grant-in-aid for Scientific Research (C) (JSPS KAKENHI Grant Number 24580139), by a Grant-in-aid for Exploratory Research (JSPS KAKENHI Grant Number 26660071), by a Grant-in-aid for Scientific Research on Priority Areas (MEXT (Ministry of Education, Culture, Sports, Science and Technology) KAKENHI Grant Number 20056016), and by the World Premier International Research Center Initiative (WPI initiative) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grants from BRAIN (the Bio-oriented Technology Research Advancement Institution).