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http://hdl.handle.net/1942/30273
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DC Field | Value | Language |
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dc.contributor.author | Postina, Rolf | - |
dc.contributor.author | Schroeder, Anja | - |
dc.contributor.author | DEWACHTER, Ilse | - |
dc.contributor.author | Bohl, Juergen | - |
dc.contributor.author | Schmitt, Ulrich | - |
dc.contributor.author | Kojro, Elzbieta | - |
dc.contributor.author | Prinzen, Claudia | - |
dc.contributor.author | Endres, Kristina | - |
dc.contributor.author | Hiemke, Christoph | - |
dc.contributor.author | Blessing, Manfred | - |
dc.contributor.author | Flamez, Pascaline | - |
dc.contributor.author | Dequenne, Antoine | - |
dc.contributor.author | Godaux, Emile | - |
dc.contributor.author | van Leuven, Fred | - |
dc.contributor.author | Fahrenholz, Falk | - |
dc.date.accessioned | 2020-01-10T08:15:35Z | - |
dc.date.available | 2020-01-10T08:15:35Z | - |
dc.date.issued | 2004 | - |
dc.date.submitted | 2020-01-09T12:11:20Z | - |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.uri | http://hdl.handle.net/1942/30273 | - |
dc.description.abstract | Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP([V717I]) increased the secretion of the neurotrophic soluble alpha-secretase-released N-terminal APP domain (APPs alpha), reduced the formation of A beta peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an alpha-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in alpha-secretase activity contributes to the development of AD. | - |
dc.description.sponsorship | The authors thank C. Haass and S. Sinha for antibodies, L. Zhang for technical assistance in behavioral studies, and M. Protschka for microinjection. Parts of this work have been supported by the Deutsche Forschungsgemeinschaft (to F. Fahrenholz and R. Postina), the Fritz Thyssen Foundation (to F. Fahrenholz and E. Kojro), and the Boehringer-Ingelheim Foundation (to M. Blessing). I. Dewachter and F. van Leuven were supported by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWOVlaanderen) and the Katholieke Universiteit Leuven Research Fund. E. Godaux was supported by the Queen Elisabeth Fund for Medical Research, Belgium. | - |
dc.language.iso | en | - |
dc.publisher | JCI | - |
dc.rights | 2020 American Society for Clinical Investigation under Creative Commons Attribution 4.0 International License (CC-BY 4.0). | - |
dc.subject.other | Alzheimer Disease | - |
dc.subject.other | Amyloid | - |
dc.subject.other | Amyloid Precursor Protein Secretases | - |
dc.subject.other | Amyloid beta-Protein Precursor | - |
dc.subject.other | Amyloidosis | - |
dc.subject.other | Animals | - |
dc.subject.other | Aspartic Acid Endopeptidases | - |
dc.subject.other | Disease Models, Animal | - |
dc.subject.other | Endopeptidases | - |
dc.subject.other | Gene Expression | - |
dc.subject.other | Hippocampus | - |
dc.subject.other | Humans | - |
dc.subject.other | Mice | - |
dc.subject.other | Mice, Transgenic | - |
dc.title | A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model | - |
dc.type | Research Report | - |
dc.identifier.epage | 1464 | - |
dc.identifier.issue | 10 | - |
dc.identifier.spage | 1456-64 | - |
dc.identifier.volume | 113 | - |
local.bibliographicCitation.jcat | A1 | - |
local.publisher.place | Ann Arbor, Michigan 48107, USA | - |
local.type.refereed | Refereed | - |
local.type.specified | Research Report | - |
dc.identifier.doi | 10.1172/JCI200420864. | - |
dc.identifier.pmid | 15146243 | - |
dc.identifier.eissn | 1558-8238 | - |
local.provider.type | PubMed | - |
local.uhasselt.uhpub | no | - |
item.fullcitation | Postina, Rolf; Schroeder, Anja; DEWACHTER, Ilse; Bohl, Juergen; Schmitt, Ulrich; Kojro, Elzbieta; Prinzen, Claudia; Endres, Kristina; Hiemke, Christoph; Blessing, Manfred; Flamez, Pascaline; Dequenne, Antoine; Godaux, Emile; van Leuven, Fred & Fahrenholz, Falk (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. | - |
item.fulltext | With Fulltext | - |
item.accessRights | Restricted Access | - |
item.contributor | Postina, Rolf | - |
item.contributor | Schroeder, Anja | - |
item.contributor | DEWACHTER, Ilse | - |
item.contributor | Bohl, Juergen | - |
item.contributor | Schmitt, Ulrich | - |
item.contributor | Kojro, Elzbieta | - |
item.contributor | Prinzen, Claudia | - |
item.contributor | Endres, Kristina | - |
item.contributor | Hiemke, Christoph | - |
item.contributor | Blessing, Manfred | - |
item.contributor | Flamez, Pascaline | - |
item.contributor | Dequenne, Antoine | - |
item.contributor | Godaux, Emile | - |
item.contributor | van Leuven, Fred | - |
item.contributor | Fahrenholz, Falk | - |
crisitem.journal.issn | 0021-9738 | - |
crisitem.journal.eissn | 1558-8238 | - |
Appears in Collections: | Research publications |
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File | Description | Size | Format | |
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Pastina Rolf 2004.pdf Restricted Access | Published version | 601.94 kB | Adobe PDF | View/Open Request a copy |
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