Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway
The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid β protein (Aβ), a small peptide derived from β- and γ-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that β- and γ-secretase activities of BACE1 and preseni...
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Veröffentlicht in: | The FASEB journal 2007-09, Vol.21 (11), p.2742-2752 |
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creator | Yoon, Il-Sang Chen, Eunice Busse, Tracy Repetto, Emanuela Lakshmana, Madepalli K Koo, Edward H Kang, David E |
description | The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid β protein (Aβ), a small peptide derived from β- and γ-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that β- and γ-secretase activities of BACE1 and presenilin, respectively, are concentrated in intracellular lipid raft microdomains. However, the manner in which APP normally traffics to lipid rafts is unknown. In this study, using transient transfection and immuno-precipitation assays, we show that the cytoplasmic domain of low-density lipoprotein receptor-related protein (LRP) interacts with APP and increases Aβ secretion and APP β-CTF (C-terminal fragment) generation by promoting BACE1-APP interaction. We also employed discontinuous sucrose density gradient ultracentrifugation to show that the LRP cytoplasmic domain-mediated effect was accompanied by greatly increased localization of APP and BACE1 to lipid raft membranes, where β- and γ-secretase activities are highly enriched. Moreover, we provide evidence that endogenous LRP is required for the normal delivery of APP to lipid rafts and Aβ generation primarily in the endocytic but not secretory pathway. These results may provide novel insights to block Aβ generation by targeting LRP-mediated delivery of APP to raft microdomains. --Yoon, I.-S., Chen, E., Busse, T., Repetto, E., Lakshmana, M. K., Koo, E. H., Kang, D. E. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway. |
doi_str_mv | 10.1096/fj.07-8114com |
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Recent studies have shown that β- and γ-secretase activities of BACE1 and presenilin, respectively, are concentrated in intracellular lipid raft microdomains. However, the manner in which APP normally traffics to lipid rafts is unknown. In this study, using transient transfection and immuno-precipitation assays, we show that the cytoplasmic domain of low-density lipoprotein receptor-related protein (LRP) interacts with APP and increases Aβ secretion and APP β-CTF (C-terminal fragment) generation by promoting BACE1-APP interaction. We also employed discontinuous sucrose density gradient ultracentrifugation to show that the LRP cytoplasmic domain-mediated effect was accompanied by greatly increased localization of APP and BACE1 to lipid raft membranes, where β- and γ-secretase activities are highly enriched. Moreover, we provide evidence that endogenous LRP is required for the normal delivery of APP to lipid rafts and Aβ generation primarily in the endocytic but not secretory pathway. These results may provide novel insights to block Aβ generation by targeting LRP-mediated delivery of APP to raft microdomains. --Yoon, I.-S., Chen, E., Busse, T., Repetto, E., Lakshmana, M. K., Koo, E. H., Kang, D. E. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.07-8114com</identifier><identifier>PMID: 17463224</identifier><language>eng</language><publisher>United States: The Federation of American Societies for Experimental Biology</publisher><subject>Alzheimer's disease ; Amyloid beta-Peptides - genetics ; Amyloid beta-Peptides - metabolism ; Amyloid Precursor Protein Secretases - genetics ; Amyloid Precursor Protein Secretases - metabolism ; Animals ; Aspartic Acid Endopeptidases - genetics ; Aspartic Acid Endopeptidases - metabolism ; BACE1 ; Cells, Cultured ; CHO Cells ; Cricetinae ; Cricetulus ; Endocytosis - physiology ; Green Fluorescent Proteins - genetics ; Green Fluorescent Proteins - metabolism ; Humans ; Immunoblotting ; Immunoprecipitation ; Kidney - metabolism ; Low Density Lipoprotein Receptor-Related Protein-1 - physiology ; Membrane Microdomains - metabolism ; Mutation - genetics ; Protein Transport ; secretase ; Signal Transduction ; siRNA ; Swedish ; Transcription, Genetic ; Transfection</subject><ispartof>The FASEB journal, 2007-09, Vol.21 (11), p.2742-2752</ispartof><rights>FASEB</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c495M-9d00242ea9022138abc43816dd50fc35a2ce5b103a09cc4f2c0c2d564cc86d163</citedby><cites>FETCH-LOGICAL-c495M-9d00242ea9022138abc43816dd50fc35a2ce5b103a09cc4f2c0c2d564cc86d163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.07-8114com$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.07-8114com$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17463224$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yoon, Il-Sang</creatorcontrib><creatorcontrib>Chen, Eunice</creatorcontrib><creatorcontrib>Busse, Tracy</creatorcontrib><creatorcontrib>Repetto, Emanuela</creatorcontrib><creatorcontrib>Lakshmana, Madepalli K</creatorcontrib><creatorcontrib>Koo, Edward H</creatorcontrib><creatorcontrib>Kang, David E</creatorcontrib><title>Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid β protein (Aβ), a small peptide derived from β- and γ-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that β- and γ-secretase activities of BACE1 and presenilin, respectively, are concentrated in intracellular lipid raft microdomains. However, the manner in which APP normally traffics to lipid rafts is unknown. In this study, using transient transfection and immuno-precipitation assays, we show that the cytoplasmic domain of low-density lipoprotein receptor-related protein (LRP) interacts with APP and increases Aβ secretion and APP β-CTF (C-terminal fragment) generation by promoting BACE1-APP interaction. We also employed discontinuous sucrose density gradient ultracentrifugation to show that the LRP cytoplasmic domain-mediated effect was accompanied by greatly increased localization of APP and BACE1 to lipid raft membranes, where β- and γ-secretase activities are highly enriched. Moreover, we provide evidence that endogenous LRP is required for the normal delivery of APP to lipid rafts and Aβ generation primarily in the endocytic but not secretory pathway. These results may provide novel insights to block Aβ generation by targeting LRP-mediated delivery of APP to raft microdomains. --Yoon, I.-S., Chen, E., Busse, T., Repetto, E., Lakshmana, M. K., Koo, E. H., Kang, D. E. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway.</description><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - genetics</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Amyloid Precursor Protein Secretases - genetics</subject><subject>Amyloid Precursor Protein Secretases - metabolism</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases - genetics</subject><subject>Aspartic Acid Endopeptidases - metabolism</subject><subject>BACE1</subject><subject>Cells, Cultured</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Endocytosis - physiology</subject><subject>Green Fluorescent Proteins - genetics</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunoprecipitation</subject><subject>Kidney - metabolism</subject><subject>Low Density Lipoprotein Receptor-Related Protein-1 - physiology</subject><subject>Membrane Microdomains - metabolism</subject><subject>Mutation - genetics</subject><subject>Protein Transport</subject><subject>secretase</subject><subject>Signal Transduction</subject><subject>siRNA</subject><subject>Swedish</subject><subject>Transcription, Genetic</subject><subject>Transfection</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtvEzEUhS0EoqGwZAuzYudy_RjHww4iwkOpuihdW44frcPMeLAdRfML-Ns4SoAdrO7jfPfoSgehlwSuCHTird9dwRJLQriJwyO0IC0DLKSAx2gBsqNYCCYv0LOcdwBAgIin6IIsuWCU8gX6uYkHbN2YQ5mbPkxxSrG4MDbJGTeVmHByvS7ONr-FWofa5UYPcx_DUXBmn3JMf5CStPfBfA_jfVPi0bZidVdyc1QfXONGG81cgmkmXR4Oen6OnnjdZ_fiXC_R3frjt9VnvLn59GX1foMN79pr3FkAyqnTHVBKmNRbw5kkwtoWvGGtpsa1WwJMQ2cM99SAobYV3BgpLBHsEr05-dZff-xdLmoI2bi-16OL-6yEpJRRxv4LUljKToi2gvgEmhRzTs6rKYVBp1kRUMeIlN8pWKpzRJV_dTbebwdn_9LnTCrw7gQcQu_mf7up9e0Huv5af6nz6ua6Hr8-HXsdlb5PIau7WwqEAUighBP2CyuwrAs</recordid><startdate>200709</startdate><enddate>200709</enddate><creator>Yoon, Il-Sang</creator><creator>Chen, Eunice</creator><creator>Busse, Tracy</creator><creator>Repetto, Emanuela</creator><creator>Lakshmana, Madepalli K</creator><creator>Koo, Edward H</creator><creator>Kang, David E</creator><general>The Federation of American Societies for Experimental Biology</general><general>Federation of American Societies for Experimental Biology</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>200709</creationdate><title>Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway</title><author>Yoon, Il-Sang ; Chen, Eunice ; Busse, Tracy ; Repetto, Emanuela ; Lakshmana, Madepalli K ; Koo, Edward H ; Kang, David E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c495M-9d00242ea9022138abc43816dd50fc35a2ce5b103a09cc4f2c0c2d564cc86d163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Alzheimer's disease</topic><topic>Amyloid beta-Peptides - genetics</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Amyloid Precursor Protein Secretases - genetics</topic><topic>Amyloid Precursor Protein Secretases - metabolism</topic><topic>Animals</topic><topic>Aspartic Acid Endopeptidases - genetics</topic><topic>Aspartic Acid Endopeptidases - metabolism</topic><topic>BACE1</topic><topic>Cells, Cultured</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Endocytosis - physiology</topic><topic>Green Fluorescent Proteins - genetics</topic><topic>Green Fluorescent Proteins - metabolism</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunoprecipitation</topic><topic>Kidney - metabolism</topic><topic>Low Density Lipoprotein Receptor-Related Protein-1 - physiology</topic><topic>Membrane Microdomains - metabolism</topic><topic>Mutation - genetics</topic><topic>Protein Transport</topic><topic>secretase</topic><topic>Signal Transduction</topic><topic>siRNA</topic><topic>Swedish</topic><topic>Transcription, Genetic</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yoon, Il-Sang</creatorcontrib><creatorcontrib>Chen, Eunice</creatorcontrib><creatorcontrib>Busse, Tracy</creatorcontrib><creatorcontrib>Repetto, Emanuela</creatorcontrib><creatorcontrib>Lakshmana, Madepalli K</creatorcontrib><creatorcontrib>Koo, Edward H</creatorcontrib><creatorcontrib>Kang, David E</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yoon, Il-Sang</au><au>Chen, Eunice</au><au>Busse, Tracy</au><au>Repetto, Emanuela</au><au>Lakshmana, Madepalli K</au><au>Koo, Edward H</au><au>Kang, David E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2007-09</date><risdate>2007</risdate><volume>21</volume><issue>11</issue><spage>2742</spage><epage>2752</epage><pages>2742-2752</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid β protein (Aβ), a small peptide derived from β- and γ-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that β- and γ-secretase activities of BACE1 and presenilin, respectively, are concentrated in intracellular lipid raft microdomains. However, the manner in which APP normally traffics to lipid rafts is unknown. In this study, using transient transfection and immuno-precipitation assays, we show that the cytoplasmic domain of low-density lipoprotein receptor-related protein (LRP) interacts with APP and increases Aβ secretion and APP β-CTF (C-terminal fragment) generation by promoting BACE1-APP interaction. We also employed discontinuous sucrose density gradient ultracentrifugation to show that the LRP cytoplasmic domain-mediated effect was accompanied by greatly increased localization of APP and BACE1 to lipid raft membranes, where β- and γ-secretase activities are highly enriched. Moreover, we provide evidence that endogenous LRP is required for the normal delivery of APP to lipid rafts and Aβ generation primarily in the endocytic but not secretory pathway. These results may provide novel insights to block Aβ generation by targeting LRP-mediated delivery of APP to raft microdomains. --Yoon, I.-S., Chen, E., Busse, T., Repetto, E., Lakshmana, M. K., Koo, E. H., Kang, D. E. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway.</abstract><cop>United States</cop><pub>The Federation of American Societies for Experimental Biology</pub><pmid>17463224</pmid><doi>10.1096/fj.07-8114com</doi><tpages>11</tpages></addata></record> |
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subjects | Alzheimer's disease Amyloid beta-Peptides - genetics Amyloid beta-Peptides - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals Aspartic Acid Endopeptidases - genetics Aspartic Acid Endopeptidases - metabolism BACE1 Cells, Cultured CHO Cells Cricetinae Cricetulus Endocytosis - physiology Green Fluorescent Proteins - genetics Green Fluorescent Proteins - metabolism Humans Immunoblotting Immunoprecipitation Kidney - metabolism Low Density Lipoprotein Receptor-Related Protein-1 - physiology Membrane Microdomains - metabolism Mutation - genetics Protein Transport secretase Signal Transduction siRNA Swedish Transcription, Genetic Transfection |
title | Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway |
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