. 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. PubMed.

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  1. This group of German and Belgian investigators has produced what is apparently the first evidence that a member of the ADAM family of proteases functions as an alpha secretase for the beta amyloid precursor protein substrate in vivo. An attractive feature of the experimental approach was the evaluation of the impacts of different degrees of overexpression of the protease. A dominant negative construct was also employed. In crosses with APP V717I transgenic mice, morphological and functional studies demonstrated clear evidence of a protective effect of moderate overexpression of ADAM10. Enhanced production of neuroprotective APPsalpha and decreased levels of beta amyloid peptides were associated with such moderate overexpression. The results provide strong rationales for the further development of clinical interventions based upon enhancements of such alpha secretase activities. Such interventions will have to hit upon an appropriate level of enhancement, as we can assume that other products of APP processing, including beta amyloid peptides, have physiological functions that also require optimal concentrations.

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