Published August 16, 2004 - More info
Alzheimer disease (AD) is characterized by excessive deposition of amyloid β-peptides (Aβ peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the α-secretase within the Aβ peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant α-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 α-secretase–released N-terminal APP domain (APPsα), reduced the formation of Aβ 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 α-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in α-secretase activity contributes to the development of AD.
Rolf Postina, Anja Schroeder, Ilse Dewachter, Juergen Bohl, Ulrich Schmitt, Elzbieta Kojro, Claudia Prinzen, Kristina Endres, Christoph Hiemke, Manfred Blessing, Pascaline Flamez, Antoine Dequenne, Emile Godaux, Fred van Leuven, Falk Fahrenholz
Original citation: J. Clin. Invest.113:1456–1464(2004). doi:10.1172/JCI20864.
Citation for this Corrigendum: J. Clin. Invest.114:142 (2004). doi:10.1172/JCI20864E1.
During the preparation of this manuscript for publication, an error was introduced into the Results section, in the fourth sentence of the paragraph beginning with “The levels of the APP-derived soluble peptides Aβ40 and Aβ42 in brains of double-transgenic mice and APP[V717I] control animals at the age of 18 weeks were quantified by specific sandwich ELISAs.” The correct sentence appears below. We regret this error.
In line ADAM10-mo × APP[V717I], Aβ40 and Aβ42 were reduced by 49% and 20%, and in line ADAM10-hi × APP[V717I], by 39% and 29%, respectively.