ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β 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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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0155400&type=printable |
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| author | Osamu Sano Maki Tsujita Yuji Shimizu Reiko Kato Aya Kobayashi Noriyuki Kioka Alan T Remaley Makoto Michikawa Kazumitsu Ueda Michinori Matsuo |
| author_facet | Osamu Sano Maki Tsujita Yuji Shimizu Reiko Kato Aya Kobayashi Noriyuki Kioka Alan T Remaley Makoto Michikawa Kazumitsu Ueda Michinori Matsuo |
| author_sort | Osamu Sano |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d3cab1916236457bb7aaa167cf0af403 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-d3cab1916236457bb7aaa167cf0af4032025-08-20T03:11:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01115e015540010.1371/journal.pone.0155400ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production.Osamu SanoMaki TsujitaYuji ShimizuReiko KatoAya KobayashiNoriyuki KiokaAlan T RemaleyMakoto MichikawaKazumitsu UedaMichinori MatsuoATP-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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0155400&type=printable |
| spellingShingle | Osamu Sano Maki Tsujita Yuji Shimizu Reiko Kato Aya Kobayashi Noriyuki Kioka Alan T Remaley Makoto Michikawa Kazumitsu Ueda Michinori Matsuo ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production. PLoS ONE |
| title | ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production. |
| title_full | ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production. |
| title_fullStr | ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production. |
| title_full_unstemmed | ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production. |
| title_short | ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production. |
| title_sort | abcg1 and abcg4 suppress γ secretase activity and amyloid β production |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0155400&type=printable |
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