. 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. In this study, the authors provide the first in- vivo demonstration of an effect on plaque formation and neuronal function by stimulating the α-secretase pathway involved in APP processing. Presently, there are two known pathways by which APP is processed: The "bad" pathway involving the β- and γ-secretases, whose activation leads to over-accumulation of the β-amyloid peptide along with plaque formation, and the "good" pathway involving α-secretase, whose activation prevents β-amyloid from forming. Currently, all major therapeutic strategies involve inhibiting the β- or γ-secretases; however, an attractive alternative would be to stimulate the α-secretase pathways. Stimulation of this pathway may be a good alternative for several reasons, one of which is that inhibiting β-secretase activity may alter Notch signaling, possibly leading to untoward side effects. In this new study, Postina et al., demonstrate that by moderately overexpressing α-secretase, they prevented to a large extent plaque formation in a mouse model of Alzheimer's disease. In addition, the authors show that overexpression of this specific α-secretase (ADAM10) reverses impaired LTP and cognitive deficits in this animal model. This study suggests that pharmacological strategies designed to stimulate the α-secretase pathway may be beneficial in treating AD, and refutes the old saying that "good guys" always finish last.

    View all comments by Troy Rohn
  2. 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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