Amyloidogenic Processing of Human Amyloid Precursor Protein in Hippocampal Neurons Devoid of Cathepsin D
βA4-Amyloid peptide, the main component of the amyloid plaques in the brain of Alzheimer's disease patients is produced from amyloid precursor protein (APP) by proteolytical processing. Several lines of evidence suggest a direct role for cathepsin D, the major endosomal/lysosomal aspartic endop...
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| Veröffentlicht in: | The Journal of biological chemistry 1996-11, Vol.271 (44), p.27241-27244 |
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| container_end_page | 27244 |
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| container_issue | 44 |
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| container_title | The Journal of biological chemistry |
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| creator | Saftig, Paul Peters, Christoph von Figura, Kurt Craessaerts, Katleen Van Leuven, Fred De Strooper, Bart |
| description | βA4-Amyloid peptide, the main component of the amyloid plaques in the brain of Alzheimer's disease patients is produced from amyloid precursor protein (APP) by proteolytical processing. Several lines of evidence suggest a direct role for cathepsin D, the major endosomal/lysosomal aspartic endopeptidase, in βA4-amyloid peptide generation. Here we tested this hypothesis using primary cultures of hippocampal neurons derived from cathepsin D-deficient (knock out) mice and expressing wild-type human APP and two clinical APP variants via recombinant Semliki Forest virus. We demonstrate APP secretory processing, production of carboxyl-terminal amyloid fragments, and secretion of the βA4-amyloid peptide in the complete absence of cathepsin D. The results rule out cathepsin D as a critical component of α-, β-, or γ-secretase and therefore as a primary target for drugs aimed at decreasing the βA4-amyloid peptide burden in Alzheimer's disease. |
| doi_str_mv | 10.1074/jbc.271.44.27241 |
| format | Article |
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Several lines of evidence suggest a direct role for cathepsin D, the major endosomal/lysosomal aspartic endopeptidase, in βA4-amyloid peptide generation. Here we tested this hypothesis using primary cultures of hippocampal neurons derived from cathepsin D-deficient (knock out) mice and expressing wild-type human APP and two clinical APP variants via recombinant Semliki Forest virus. We demonstrate APP secretory processing, production of carboxyl-terminal amyloid fragments, and secretion of the βA4-amyloid peptide in the complete absence of cathepsin D. The results rule out cathepsin D as a critical component of α-, β-, or γ-secretase and therefore as a primary target for drugs aimed at decreasing the βA4-amyloid peptide burden in Alzheimer's disease.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.271.44.27241</identifier><identifier>PMID: 8910296</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Amyloid beta-Peptides - biosynthesis ; Amyloid beta-Peptides - chemistry ; Amyloid beta-Protein Precursor - biosynthesis ; Amyloid beta-Protein Precursor - chemistry ; Amyloid beta-Protein Precursor - metabolism ; Animals ; Base Sequence ; Cathepsin D - deficiency ; Cells, Cultured ; Crosses, Genetic ; DNA Primers ; Genetic Variation ; Heterozygote ; Hippocampus - metabolism ; Humans ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Neurons - metabolism ; Polymerase Chain Reaction ; Protein Processing, Post-Translational ; Semliki forest virus ; Transfection</subject><ispartof>The Journal of biological chemistry, 1996-11, Vol.271 (44), p.27241-27244</ispartof><rights>1996 © 1996 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-f37ff8b15490736ccd7eb61326284af0581727c30ed0f04805aa0b0e6e69de113</citedby><cites>FETCH-LOGICAL-c447t-f37ff8b15490736ccd7eb61326284af0581727c30ed0f04805aa0b0e6e69de113</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8910296$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Saftig, Paul</creatorcontrib><creatorcontrib>Peters, Christoph</creatorcontrib><creatorcontrib>von Figura, Kurt</creatorcontrib><creatorcontrib>Craessaerts, Katleen</creatorcontrib><creatorcontrib>Van Leuven, Fred</creatorcontrib><creatorcontrib>De Strooper, Bart</creatorcontrib><title>Amyloidogenic Processing of Human Amyloid Precursor Protein in Hippocampal Neurons Devoid of Cathepsin D</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>βA4-Amyloid peptide, the main component of the amyloid plaques in the brain of Alzheimer's disease patients is produced from amyloid precursor protein (APP) by proteolytical processing. 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Peters, Christoph ; von Figura, Kurt ; Craessaerts, Katleen ; Van Leuven, Fred ; De Strooper, Bart</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-f37ff8b15490736ccd7eb61326284af0581727c30ed0f04805aa0b0e6e69de113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Amino Acid Sequence</topic><topic>Amyloid beta-Peptides - biosynthesis</topic><topic>Amyloid beta-Peptides - chemistry</topic><topic>Amyloid beta-Protein Precursor - biosynthesis</topic><topic>Amyloid beta-Protein Precursor - chemistry</topic><topic>Amyloid beta-Protein Precursor - metabolism</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Cathepsin D - deficiency</topic><topic>Cells, Cultured</topic><topic>Crosses, Genetic</topic><topic>DNA Primers</topic><topic>Genetic Variation</topic><topic>Heterozygote</topic><topic>Hippocampus - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Molecular Sequence Data</topic><topic>Neurons - metabolism</topic><topic>Polymerase Chain Reaction</topic><topic>Protein Processing, Post-Translational</topic><topic>Semliki forest virus</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Saftig, Paul</creatorcontrib><creatorcontrib>Peters, Christoph</creatorcontrib><creatorcontrib>von Figura, Kurt</creatorcontrib><creatorcontrib>Craessaerts, Katleen</creatorcontrib><creatorcontrib>Van Leuven, Fred</creatorcontrib><creatorcontrib>De Strooper, Bart</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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 Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Saftig, Paul</au><au>Peters, Christoph</au><au>von Figura, Kurt</au><au>Craessaerts, Katleen</au><au>Van Leuven, Fred</au><au>De Strooper, Bart</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amyloidogenic Processing of Human Amyloid Precursor Protein in Hippocampal Neurons Devoid of Cathepsin D</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>1996-11-01</date><risdate>1996</risdate><volume>271</volume><issue>44</issue><spage>27241</spage><epage>27244</epage><pages>27241-27244</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>βA4-Amyloid peptide, the main component of the amyloid plaques in the brain of Alzheimer's disease patients is produced from amyloid precursor protein (APP) by proteolytical processing. 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| ispartof | The Journal of biological chemistry, 1996-11, Vol.271 (44), p.27241-27244 |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Amino Acid Sequence Amyloid beta-Peptides - biosynthesis Amyloid beta-Peptides - chemistry Amyloid beta-Protein Precursor - biosynthesis Amyloid beta-Protein Precursor - chemistry Amyloid beta-Protein Precursor - metabolism Animals Base Sequence Cathepsin D - deficiency Cells, Cultured Crosses, Genetic DNA Primers Genetic Variation Heterozygote Hippocampus - metabolism Humans Mice Mice, Knockout Molecular Sequence Data Neurons - metabolism Polymerase Chain Reaction Protein Processing, Post-Translational Semliki forest virus Transfection |
| title | Amyloidogenic Processing of Human Amyloid Precursor Protein in Hippocampal Neurons Devoid of Cathepsin D |
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