We proposed that downregulation of the p75 neurotrophin receptor (p75), a receptor that promotes atrophy and apoptosis of cholinergic neurons, may improve cognitive performance in Alzheimer’s model mice. We compared spatial learning in 14-month-old Tg2576 mice to Tg2576 mice that were heterozygous for a null mutation in p75. Tg2576 mice develop impaired spatial learning, from 10 months of age, accompanied by considerable amyloid deposition in the brain. To ensure that all mice in our study had identical genetic backgrounds, Tg2576 and p75 knockout mice were each backcrossed onto the inbred 129Sv strain until they achieved congenicity with the strain. They were than mated together, and Tg2576 mice that were heterozygous for p75 were selected and retained until the age of 14 months. Mice were then tested on the Barnes Maze, a test of spatial learning and memory that reflects hippocampal function. As expected, 14-month-old Tg2576 mice performed poorly. After 8 days, only 7% of Tg2576 mice had reached the learning criterion. By the end of the 10-day trial, only 27% had reached the criterion. In contrast, 73% of 14-month-old Tg2576/p75± mice reached criterion by day 10. This difference in performance was highly significant (p=0.007; Wilcoxon matched pairs test). There was no change, however, in the level of A-beta amyloid peptide in the brain. Thus, knockdown of p75 improved cognition in Tg2576 mice independently of amyloid peptide levels. At least part of the improvement is mediated by the cholinergic forebrain system .
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