Memory Impairment in Transgenic Alzheimer Mice Requires Cellular Prion Protein

Soluble oligomers of the amyloid-beta (A beta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic A beta oligomers bind to cellular prion protein (PrPC) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric A beta peptide. We hypothesized that PrPC is essential for the ability of brain-derived A beta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1 Delta E9 into Prnp(-/-) mice to examine the necessity of PrPC for AD-related phenotypes. Neither APP expression nor A beta level is altered by PrPC absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrPC expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/ PSen1 Delta E9 transgenic mice. The AD transgenic mice with intact PrPC expression exhibit deficits in spatial learning and memory. Mice lacking PrPC, but containing A beta plaque derived from APPswe/PSen1 Delta E9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrPC expression dissociates A beta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrPC.