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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| 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. |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0155400</identifier><identifier>PMID: 27196068</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alzheimer Disease - genetics ; Alzheimer Disease - metabolism ; Alzheimer's disease ; Amyloid beta-Peptides - biosynthesis ; Amyloid precursor protein ; Amyloid Precursor Protein Secretases - genetics ; Amyloid Precursor Protein Secretases - metabolism ; Animals ; Apolipoproteins ; ATP Binding Cassette Transporter, Sub-Family G - genetics ; ATP Binding Cassette Transporter, Sub-Family G - metabolism ; ATP Binding Cassette Transporter, Sub-Family G, Member 1 - genetics ; ATP Binding Cassette Transporter, Sub-Family G, Member 1 - metabolism ; Biochemistry ; Biology and Life Sciences ; Caveolin 1 - metabolism ; Cell Line, Tumor ; Cell Membrane - metabolism ; Cell surface ; Central nervous system ; Cerebrospinal fluid ; Cholesterol ; Efflux ; Gene Silencing ; HEK293 Cells ; Humans ; Laboratories ; Life sciences ; Lipids ; Lipoproteins ; Localization ; Lysine ; Medical treatment ; Medicine and Health Sciences ; Membrane Glycoproteins - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Neuronal-glial interactions ; Pathogenesis ; Proteins ; Research and Analysis Methods ; RNA Interference ; Rodents ; Secretase ; Secretion ; Statins ; University graduates</subject><ispartof>PloS one, 2016-05, Vol.11 (5), p.e0155400-e0155400</ispartof><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c636t-6cc5c892b7503c2443fc28927dc1501d4bbcd26a1a21b58903e328ec1506e9893</citedby><cites>FETCH-LOGICAL-c636t-6cc5c892b7503c2443fc28927dc1501d4bbcd26a1a21b58903e328ec1506e9893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872999/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872999/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27196068$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Jo, Dong-Gyu</contributor><creatorcontrib>Sano, Osamu</creatorcontrib><creatorcontrib>Tsujita, Maki</creatorcontrib><creatorcontrib>Shimizu, Yuji</creatorcontrib><creatorcontrib>Kato, Reiko</creatorcontrib><creatorcontrib>Kobayashi, Aya</creatorcontrib><creatorcontrib>Kioka, Noriyuki</creatorcontrib><creatorcontrib>Remaley, Alan T</creatorcontrib><creatorcontrib>Michikawa, Makoto</creatorcontrib><creatorcontrib>Ueda, Kazumitsu</creatorcontrib><creatorcontrib>Matsuo, Michinori</creatorcontrib><title>ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production</title><title>PloS one</title><addtitle>PLoS One</addtitle><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.</description><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - biosynthesis</subject><subject>Amyloid precursor protein</subject><subject>Amyloid Precursor Protein Secretases - genetics</subject><subject>Amyloid Precursor Protein Secretases - metabolism</subject><subject>Animals</subject><subject>Apolipoproteins</subject><subject>ATP Binding Cassette Transporter, Sub-Family G - genetics</subject><subject>ATP Binding Cassette Transporter, Sub-Family G - metabolism</subject><subject>ATP Binding Cassette Transporter, Sub-Family G, Member 1 - genetics</subject><subject>ATP Binding Cassette Transporter, Sub-Family G, Member 1 - metabolism</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Caveolin 1 - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sano, Osamu</au><au>Tsujita, Maki</au><au>Shimizu, Yuji</au><au>Kato, Reiko</au><au>Kobayashi, Aya</au><au>Kioka, Noriyuki</au><au>Remaley, Alan T</au><au>Michikawa, Makoto</au><au>Ueda, Kazumitsu</au><au>Matsuo, Michinori</au><au>Jo, Dong-Gyu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-05-19</date><risdate>2016</risdate><volume>11</volume><issue>5</issue><spage>e0155400</spage><epage>e0155400</epage><pages>e0155400-e0155400</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27196068</pmid><doi>10.1371/journal.pone.0155400</doi><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1790062897 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer's disease Amyloid beta-Peptides - biosynthesis Amyloid precursor protein Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals Apolipoproteins ATP Binding Cassette Transporter, Sub-Family G - genetics ATP Binding Cassette Transporter, Sub-Family G - metabolism ATP Binding Cassette Transporter, Sub-Family G, Member 1 - genetics ATP Binding Cassette Transporter, Sub-Family G, Member 1 - metabolism Biochemistry Biology and Life Sciences Caveolin 1 - metabolism Cell Line, Tumor Cell Membrane - metabolism Cell surface Central nervous system Cerebrospinal fluid Cholesterol Efflux Gene Silencing HEK293 Cells Humans Laboratories Life sciences Lipids Lipoproteins Localization Lysine Medical treatment Medicine and Health Sciences Membrane Glycoproteins - metabolism Mice Mice, Inbred C57BL Mice, Knockout Mutation Neuronal-glial interactions Pathogenesis Proteins Research and Analysis Methods RNA Interference Rodents Secretase Secretion Statins University graduates |
| title | ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T14%3A47%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=ABCG1%20and%20ABCG4%20Suppress%20%CE%B3-Secretase%20Activity%20and%20Amyloid%20%CE%B2%20Production&rft.jtitle=PloS%20one&rft.au=Sano,%20Osamu&rft.date=2016-05-19&rft.volume=11&rft.issue=5&rft.spage=e0155400&rft.epage=e0155400&rft.pages=e0155400-e0155400&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0155400&rft_dat=%3Cproquest_plos_%3E1790464791%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1790062897&rft_id=info:pmid/27196068&rft_doaj_id=oai_doaj_org_article_d3cab1916236457bb7aaa167cf0af403&rfr_iscdi=true |