P1-001: Memantine reverses cognitive deficits in transgenic mice with both plaques and tangles

Abstract

Alzheimer's disease (AD) is generally believed to result from the progressive accumulation of beta amyloid plaques and neurofibrillary tangles, which may cause or occur coincident with significant neuronal loss. Memantine, an uncompetitive NMDA receptor antagonist, is widely–prescribed in humans with AD, although the effect of this drug on progressive neuropathology remains unknown. In this study, using a battery of cognitive tasks, the effect of memantine was tested in triple transgenic mice which harbor mutations in three genes relevant to AD pathology (PS1M146V, APPSwe and tauP301L).These mice develop both plaques and tangles in a region–specific and age–progressive manner and also exhibit learning impairment and synaptic dysfunction. Memantine (30 mg/kg/day) was administered orally via drinking water either from 2–12 months or from 9–12 months of age in “preventative” or “reversal” trials, respectively. We found that in both treatment paradigms, memantine significantly prevented memory deficits in the Morris water maze, inhibitory avoidance and novel object recognition tasks compared to vehicle–treated transgenic mice. These findings carry two important implications. First, memantine is able to prevent the progressive decline in cognitive functioning in these mice. Second, and perhaps more importantly, memantine is able to slow or reverse established cognitive deficits in older transgenic mice, confirming memantine's use in individuals with established AD pathology.