Converging evidence links abnormally high brain concentrations of amyloid-β peptides (Aβ) to the pathology of Alzheimer's disease (AD). Lowering brain Aβ levels, therefore, is a therapeutic strategy for the treatment of AD. Neuronal neprilysin upregulation led to increased degradation of Aβ, reduced the formation of Aβ-plaques and the associated cytopathology, but whether overexpression of neprilysin can improve cognition is unknown. We show that neuronal overexpression of neprilysin improved the Morris water maze memory performance in mice with memory deficits resulting from overexpression of the AD-causing mutated human amyloid precursor protein (APP). This improvement was associated with decreased brain levels of Aβ and with unchanged endoproteolytic processing of APP. These results provide the evidence that lowering of brain Aβ levels by increasing its degradation can improve cognitive functions in vivo, and suggest that increasing the activity of neprilysin in brain may be effective in preventing cognitive decline in AD.