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Soluble oligomers of the amyloid-β (Aβ) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Aβ oligomers bind to cellular prion protein (PrPC) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Aβ peptide. We hypothesized that PrPC is essential for the ability of brain-derived Aβ to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1ΔE9 into Prnp-/- mice to examine the necessity of PrPC for AD-related phenotypes. Neither APP expression nor Aβ 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/PSen1ΔE9 transgenic mice. The AD transgenic mice with intact PrPC expression exhibit deficits in spatial learning and memory. Mice lacking PrPC, but containing Aβ plaque derived from APPswe/PSen1ΔE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrPC expression dissociates Aβ accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrPC. [ABSTRACT FROM AUTHOR]

Replying to: H. W. Kessels, L. N. Nguyen, S. Nabavi & R. Malinow 466, 10.1038/nature09217 (2010)Amyloid-? oligomers are correlated with Alzheimer’s disease progression and suppress synaptic plasticity. Through unbiased expression cloning, we identified cellular prion protein (PrPC) as an amyloid-? oligomer binding protein. PrPC was necessary for acute amyloid-?(1?42) (A?42) oligomer suppression of synaptic plasticity; thus, it becomes critical to explore the importance of PrPC in a range of Alzheimer’s-disease-related deficits. Transgenic Alzheimer’s disease model mice show deficits of spatial learning and memory, so the most direct assessment of PrPC will monitor memory in transgenic Alzheimer’s disease model mice deficient for PrPC. In this paradigm, amyloid-? species are produced endogenously and the brain is exposed chronically over months. Recently, we have found that deletion of PrPC from APPswe/PSen1?E9 transgenic mice restores spatial learning and memory without altering amyloid-?. Furthermore, the early death, synapse loss and serotonin axonal degeneration of transgenic Alzheimer’s disease mice require PrPC (ref. 6). Kessels et al. examine PrPC in alternative paradigms. [ABSTRACT FROM AUTHOR]