title: A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model.
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.
authors.affiliation: Institute of Biochemistry, University of Mainz, Mainz, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Postina
authors.forename: Anja
authors.initials: A
authors.lastname: Schroeder
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.forename: Juergen
authors.initials: J
authors.lastname: Bohl
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kojro
authors.forename: Claudia
authors.initials: C
authors.lastname: Prinzen
authors.forename: Kristina
authors.initials: K
authors.lastname: Endres
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Manfred
authors.initials: M
authors.lastname: Blessing
authors.forename: Pascaline
authors.initials: P
authors.lastname: Flamez
authors.forename: Antoine
authors.initials: A
authors.lastname: Dequenne
authors.forename: Emile
authors.initials: E
authors.lastname: Godaux
authors.forename: Fred
authors.initials: F
authors.lastname: van Leuven
authors.forename: Falk
authors.initials: F
authors.lastname: Fahrenholz
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse