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Experimental Genetics Group

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

J Clin Invest. 2004 May;113(10):1456-64. Erratum in: J Clin Invest. 2004 Aug;114(4):598.

Postina R1, Schroeder A1, Dewachter I2, Bohl J3, Schmitt U4, Kojro E1, Prinzen C1, Endres K1, Hiemke C4, Blessing M5,6, Flamez P7, Dequenne A7, Godaux E7, van Leuven F2, Fahrenholz F1.

1Institute of Biochemistry, University of Mainz, Mainz, Germany.
2Experimental Genetics Group, Department of Human Genetics, K.U.Leuven, Leuven, Belgium.
3Department of Neuropathology, University of Mainz, Mainz, Germany.
4Department of Psychiatry, University of Mainz, Mainz, Germany.
5Department of Pathophysiology, University of Mainz, Mainz.
6Center for Biotechnology and Biomedicine (BBZ), Department of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
7Laboratory of Neuroscience, University of Mons-Hainaut, Mons, Belgium.

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.

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