Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking

Memantine, an uncompetitive glutamatergic N-methyl-o-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-beta peptide (A beta) 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 A beta production. Memantine was administered to 9-month -old Tg2576 mice, a transgenic mouse model of AD, at 10 or 20 mg/ kg/day in drinking water for 1 month. Memantine significantly reduced the amounts of both CHAPS -soluble and CHAPS -insoluble A beta in the brains of Tg2576 mice. Memantine at 10 mg/kg/day for 1 month also reduced the levels of insoluble A beta 42 in the brains of aged F344 rats. Moreover, memantine reduced A beta and sAPP beta levels in conditioned media from rat primary cortical cultures without affecting the enzymatic activities of a-secretase, beta-secretase, or gamma-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 A beta both in AD models and in aged animals, and that memantine affects the endocytosis pathway of APP, which is required for beta-secretasemediated cleavage. This leads to a reduction in All production. These results suggest that memantine reduces A beta production and plaque deposition through the regulation of intracellular trafficking of APP.