| Proprotein convertase activity contributes to the processing of the Alzheimer's beta-amyloid precursor protein in human cells: evidence for a role of the prohormone convertase PC7 in the constitutive alpha-secretase pathway. | |
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MedLine Citation:
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PMID: 10537065 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The physiological maturation of the beta-amyloid precursor protein (betaAPP) leads to the secretion of a fragment termed APPalpha, after cleavage by a proteolytic enzyme called-secretase. In Alzheimer's disease, betaAPP undergoes exacerbated proteolytic attacks by beta- and gamma-secretases, which liberate a readily aggregatable 40-42-amino acid peptide called AP. We show here that overexpression of the prohormone convertase PC7 triggers increased secretion of APPalpha and lowers both Abeta40 and Abeta42 recoveries. Overexpression of alpha1-antitrypsin Portland (alpha1-PDX), which blocks mammalian precursor convertases of the constitutive secretory pathway, reverses the PC7-induced APPalpha increase as well as the decrease of Abeta40/42 in HEK293 cells. It is interesting that alpha1-PDX also lowers the level of APPalpha endogenously produced by mock-transfected HEK293 cells. Finally, a Jurkat clone stably expressing alpha1-PDX produces noticeably lower amounts of APPalpha. Therefore, this serpin affects endogenous a-secretase activity/pathway in distinct cell types. By contrast, alpha1-PDX does not alter the processing of presenilin 1 or its mutated congeners linked to some familial forms of Alzheimer's disease. Altogether, we demonstrate that a prohormone convertase participates in the alpha-secretase pathway of betaAPP maturation in human cells and concomitantly contributes to slowing the pathogenic route leading to the formation of Abeta. Our data strongly suggest that PC7 could fulfill such a role. |
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Authors:
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E Lopez-Perez; N G Seidah; F Checler |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of neurochemistry Volume: 73 ISSN: 0022-3042 ISO Abbreviation: J. Neurochem. Publication Date: 1999 Nov |
Date Detail:
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Created Date: 1999-11-05 Completed Date: 1999-11-05 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 2985190R Medline TA: J Neurochem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 2056-62 Citation Subset: IM |
Affiliation:
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IPMC du CNRS, UPR 411, Sophia Antipolis, Valbonne, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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metabolism* Amyloid Precursor Protein Secretases Amyloid beta-Protein / metabolism Amyloid beta-Protein Precursor / metabolism* Animals Aspartic Acid Endopeptidases Cell Line Endopeptidases / metabolism* Enzyme Inhibitors / pharmacology Furin Gene Deletion Gene Expression Humans Jurkat Cells Kinetics Membrane Proteins / genetics Mutation Peptide Fragments / metabolism Presenilin-1 Rats Subtilisins / antagonists & inhibitors, genetics, metabolism* Transfection alpha 1-Antitrypsin / genetics, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein; 0/Amyloid beta-Protein Precursor; 0/Enzyme Inhibitors; 0/Membrane Proteins; 0/PSEN1 protein, human; 0/Peptide Fragments; 0/Presenilin-1; 0/alpha 1-Antitrypsin; 0/alpha 1-antitrypsin Portland; EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.-/Endopeptidases; EC 3.4.21.-/Subtilisins; EC 3.4.21.75/Furin; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.23.46/BACE1 protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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