Memantine is a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that stabilizes cognitive, functional, and behavioral decline in patients with moderate to severe Alzheimer's disease (AD). In AD, the extracellular deposition of fibrillogenic amyloid-beta peptides (Abeta) occurs as a result of aberrant processing of the full-length Abeta precursor protein (APP). Memantine protects neurons from the neurotoxic effects of Abeta and improves cognition in transgenic mice with high brain levels of Abeta. However, it is unknown how memantine protects cells against neurodegeneration and affects APP processing and Abeta production. We report the effects of memantine in three different systems. In human neuroblastoma cells, memantine, at therapeutically relevant concentrations (1-4 muM), decreased levels of secreted APP and Abeta(1-40). Levels of the potentially amylodogenic Abeta(1-42) were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered Abeta(1-42) secretion. At the concentrations used, memantine treatment was not toxic to neuroblastoma or primary cultures and increased cell viability and/or metabolic activity under certain conditions. In APP/presenilin-1 (PS1) transgenic mice exhibiting high brain levels of Abeta(1-42), oral dosing of memantine (20 mg/kg/day for 8 days) produced a plasma drug concentration of 0.96 microM and significantly reduced the cortical levels of soluble Abeta(1-42). The ratio of Abeta(1-40)/Abeta(1-42) increased in treated mice, suggesting effects on the gamma-secretase complex. Thus, memantine reduces the levels of Abeta peptides at therapeutic concentrations and may inhibit the accumulation of fibrillogenic Abeta in mammalian brains. Memantine's ability to preserve neuronal cells against neurodegeneration, to increase metabolic activity, and to lower Abeta level has therapeutic implications for neurodegenerative disorders.