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Title: | A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model | Authors: | 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 |
Issue Date: | 2004 | Publisher: | JCI | 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. | Keywords: | Alzheimer Disease;Amyloid;Amyloid Precursor Protein Secretases;Amyloid beta-Protein Precursor;Amyloidosis;Animals;Aspartic Acid Endopeptidases;Disease Models, Animal;Endopeptidases;Gene Expression;Hippocampus;Humans;Mice;Mice, Transgenic | Document URI: | http://hdl.handle.net/1942/30273 | ISSN: | 0021-9738 | e-ISSN: | 1558-8238 | DOI: | 10.1172/JCI200420864. | Rights: | 2020 American Society for Clinical Investigation under Creative Commons Attribution 4.0 International License (CC-BY 4.0). | Category: | A1 | Type: | Research Report |
Appears in Collections: | Research publications |
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