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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, Freddy
Fahrenholz, Falk #
Issue Date: May-2004
Series Title: Journal of Clinical Investigation vol:113 issue:10 pages:1456-64
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.
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Associated Laboratories - miscellaneous (-)
× corresponding author
# (joint) last author

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