Memantine Effects on Amyloid Plaque Load and Cognition in APP/SP1 Transgenic Mice

Abstract ID 91679 Poster Board 117 Background: In earlier studies, the effects of various drugs were tested on wild-type mice using a Barnes Maze to assess spatial learning and memory by measuring time and distance to enter an Escape Box (EsB). Neuropathological features of Alzheimer's disease (AD) include accumulation of amyloid-β (Aβ) aggregates in the brain parenchyma as neuritic plaques and in the cerebrovasculature as cerebral amyloid angiopathy (CAA), which is associated with neurodegeneration and cognitive impairment. Memantine, an NMDA glutamate receptor antagonist, is used to treat moderate to severe dementia associated with AD, but it is also implicated in excitotoxicity and neuronal cell death. A previous animal study showed that memantine reduced amyloid plaque load in APP/PS1 transgenic mice, but it is not clear if it has differential effects on deposition of neuritic plaques vs CAA in these mice. In this study, we assessed the effects of chronic exposure to memantine on spatial learning and memory utilizing a Barnes Maze test and Aβ plaque load in the APP/PS1 transgenic mouse model of AD. Methods: APP/PS1 transgenic and littermate wild-type mice were divided into four cohorts receiving memantine: control, memantine 10 mg/kg/day, memantine 20 mg/kg/day, and memantine 50 mg/kg/day, dissolved in drinking water, from 5 months of age for 6 months. At 6 months of age, all animals began Barnes Maze testing, 3 times per week, to assess spatial learning and memory, measuring distance traveled and time to enter the escape box (EsB), all video recorded and analyzed using ggpplot2 in RStudio to represent the collected data. At 11 months of age, animal brains were fixed and stained with methoxy-X34 and resorufin. Fixed, whole brains were coronally sectioned, images of various regions were photographed, and Aβ plaque load was assessed using ImageJ software. Results: Barnes Maze results suggest that increased doses of memantine produced a protective effect that seemed to obtund development of cognition issues associated with spatial learning and memory in female mice, an effect not apparent in male mice. This was noted by a difference in time to enter the EsB seen in transgenic male mice relative to the wild type male mice, a difference not noted in female transgenic mice relative to the wild type female mice. Fluorescent labeling with methoxy-X34 and resorufin showed that Aβ aggregates were detectable throughout pial arterioles and parenchymal brain tissues in APP/PS1 transgenic mice. We found that treatment of APP/PS1 mice had no significant effects of Aβ load when assessed in the prefrontal cortex, piriform cortex, and hippocampus. Conclusions: 1. Memantine, administered early in life and chronically taken, may obtund the development of cognition issues. 2. Male transgenic mice seem less responsive to memantine's benefits than female mice. 3. Long-term treatment with memantine had differential effects on amyloid load in forms of neuritic plaques vs CAA in this transgenic mouse model.