Memantine Lowers Amyloid-β Peptide Levels in Neuronal Cultures and in APP/PS1 Transgenic Mice

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 (A beta) occurs as a result of aberrant processing of the full-length A beta precursor protein (APP). Memantine protects neurons from the neurotoxic effects of A beta and improves cognition in transgenic mice with high brain levels of A beta. However, it is unknown how memantine protects cells against neurodegeneration and affects APP processing and A beta production. We report the effects of memantine in three different systems. In human neuroblastoma cells, memantine, at therapeutically relevant concentrations (1-4 mu M), decreased levels of secreted APP and A beta(1-40). Levels of the potentially amylodogenic A beta(1-42) were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered A beta(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 A beta(1-42), oral dosing of memantine (20 mg/kg/day for 8 days) produced a plasma drug concentration of 0.96 mu M and significantly reduced the cortical levels of soluble A beta(1-42). The ratio of A beta(1-40)/A beta(1-42) increased in treated mice, suggesting effects on the gamma-secretase complex. Thus, memantine reduces the levels of A beta peptides at therapeutic concentrations and may inhibit the accumulation of fibrillogenic A beta in mammalian brains. Memantine's ability to preserve neuronal cells against neurodegeneration, to increase metabolic activity, and to lower A beta level has therapeutic implications for neurodegenerative disorders. (C) 2009 Wiley-Liss, Inc.