ABSTRACT
Memantine, an uncompetitive glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as medication for the treatment of Alzheimer's disease (AD). It has been reported that memantine reduces amyloid-ß peptide (Aß) levels in both neuronal cultures and in brains of animal models of AD. However, the underlying mechanism of these effects is unclear. Here we examined the effect of memantine on Aß production. Memantine was administered to 9-month-old Tg2576 mice, a transgenic mouse model of AD, at 10 or 20mg/kg/day in drinking water for 1 month. Memantine significantly reduced the amounts of both CHAPS-soluble and CHAPS-insoluble Aß in the brains of Tg2576 mice. Memantine at 10mg/kg/day for 1 month also reduced the levels of insoluble Aß42 in the brains of aged F344 rats. Moreover, memantine reduced Aß and sAPPß levels in conditioned media from rat primary cortical cultures without affecting the enzymatic activities of α-secretase, ß-secretase, or γ-secretase. Notably, in a cell-surface biotinylation assay, memantine increased the amount of amyloid precursor protein (APP) at the cell surface without changing the total amount of APP. Collectively, our results indicate that chronic treatment with memantine reduces the levels of Aß both in AD models and in aged animals, and that memantine affects the endocytosis pathway of APP, which is required for ß-secretase-mediated cleavage. This leads to a reduction in Aß production. These results suggest that memantine reduces Aß production and plaque deposition through the regulation of intracellular trafficking of APP.
