A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

6533b7cffe1ef96bd12598cf

RESEARCH PRODUCT

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

Ilse Dewachter Kristina Endres Rolf Postina Anja Schroeder Antoine Dequenne Fred Van Leuven Falk Fahrenholz Elzbieta Kojro Christoph Hiemke Pascaline Flamez Manfred Blessing Claudia Prinzen Juergen Bohl Ulrich Schmitt Emile Godaux

subject

Genetically modified mouse Pathology medicine.medical_specialty Amyloid Amyloid ADAM10 BACE1-AS Gene Expression Mice Transgenic Hippocampus Article Amyloid beta-Protein Precursor Mice Alzheimer Disease Endopeptidases Amyloid precursor protein medicine Animals Aspartic Acid Endopeptidases Humans biology business.industry P3 peptide Amyloidosis General Medicine medicine.disease Cell biology Enzyme Activation Disease Models Animal Commentary biology.protein Erratum Alzheimer's disease Amyloid Precursor Protein Secretases business Amyloid precursor protein secretase

description

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.

year	journal	country	edition	language
2004-08-16	Journal of Clinical Investigation

https://doi.org/10.1172/jci20864e1