Brain beta-amyloid plaques are principal targets for the development of treatments designed to slow the progression of Alzheimer's disease. Intracranial injections of synthetic beta-amyloid peptide (Abeta(42)) in transgenic mice expressing the Alzheimer's disease-causing Swedish APP double mutations increased neuronal levels of neprilysin, a metalloendopeptidase that degrades Abeta(42) in vivo, on mRNA and protein level. This increase was associated with significant reductions in brain levels of Abeta and with almost complete prevention of amyloid plaque formation throughout the brain. In addition, astrogliosis normally associated with amyloidosis was significantly reduced. Our results suggest that up-regulation of neprilysin in brain may represent an opportunity to reduce or prevent amyloid plaque formation in vivo.