Cerebral deposition of β-amyloid (Aβ) peptides is an invariant pathological hallmark in brains of patients with Alzheimer's disease (AD) and transgenic mice coexpressing familial AD-linked APP and PS1 variants. We now report that exposure of transgenic mice to an "enriched environment" results in pronounced reductions in cerebral Aβ levels and amyloid deposits, compared to animals raised under "standard housing" conditions. The enzymatic activity of an Aβ-degrading endopeptidase, neprilysin, is elevated in the brains of "enriched" mice and inversely correlated with amyloid burden. Moreover, DNA microarray analysis revealed selective upregulation in levels of transcripts encoded by genes associated with learning and memory, vasculogenesis, neurogenesis, cell survival pathways, Aβ sequestration, and prostaglandin synthesis. These studies provide evidence that environmental enrichment leads to reductions in steady-state levels of cerebral Aβ peptides and amyloid deposition and selective upregulation in levels of specific transcripts in brains of transgenic mice.