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 a-secretase–released N-terminal APP domain (APPsa), reduced the formation of Aß 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.