title: ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production.
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.
authors.affiliation: Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Kyoto University Graduate School of Agriculture, Kyoto, 606-8502, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sano
authors.affiliation: Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Tsujita
authors.affiliation: Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Kyoto University Graduate School of Agriculture, Kyoto, 606-8502, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Kyoto University Graduate School of Agriculture, Kyoto, 606-8502, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kato
authors.affiliation: Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Kyoto University Graduate School of Agriculture, Kyoto, 606-8502, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Kyoto University Graduate School of Agriculture, Kyoto, 606-8502, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kioka
authors.affiliation: Lipoprotein Metabolism Section, NHLBI, National Institutes of Health, Bethesda, MD, 20892-1508, United States of America.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.affiliation: Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
authors.affiliation: Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Kyoto University Graduate School of Agriculture, Kyoto, 606-8502, Japan.|iCeMS, Kyoto University, Kyoto, 606-8502, Japan.
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ueda
authors.affiliation: iCeMS, Kyoto University, Kyoto, 606-8502, Japan.|Department of Food and Nutrition, Faculty of Home Economics, Kyoto Women's University, Kyoto, 605-8501, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D000070996:ATP Binding Cassette Transporter, Subfamily G / Q000235:genetics / Q000378:metabolism*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D034622:RNA Interference
chemical_list: C419353:ABCG1 protein, human; C439766:ABCG4 protein, human; D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D016229:Amyloid beta-Peptides; C495540:CAV1 protein, human; D051242:Caveolin 1; D008562:Membrane Glycoproteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D008239:Lysine