The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid-beta protein precursor (AbetaPP) within the region of the amyloid-beta peptides to prevent their formation and aggregation in the brain. Members of the ADAM family (a disintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. We recently demonstrated that overexpression of ADAM10 in mice transgenic for human AbetaPP (ADAM10 x APP[V717I]) alleviated functional deficits related to Alzheimer's disease. To further demonstrate that this is due to the specific activity of alpha-secretase, we characterized mice overexpressing an inactive form of ADAM10 (ADAM10[E384A]; ADAM10-dn). Three lines of mice (controls (C57Bl/6 x FVB), APP[V717I[ transgenics and ADAM10-dn x APP[V717I] double-transgenics) were investigated with respect to learning and memory in the Morris water maze. Double-transgenic mice overexpressing ADAM10-dn behaved similar to APP[V717I] overexpressing mice. This provides further evidence that ADAM10 in vivo by its enzymatic activity is able to counteract cognitive deficits. Stimulation of alpha-secretase activity might thus be a suitable approach to study treatment strategies of Alzheimer's disease.