Cellular prion protein mediates the toxicity of beta-amyloid oligomers: implications for Alzheimer disease

Abstract

Alzheimer disease (AD) is the most common cause of age-related dementia, affecting more than 25 million people worldwide. The accumulation of insoluble beta-amyloid (Abeta) plaques in the brain has long been considered central to the pathogenesis of AD. However, recent evidence suggests that soluble oligomeric assemblies of Abeta may be of greater importance. beta-Amyloid oligomers have been found to be potent synaptotoxins, but the mechanism by which they exert their action has remained elusive. Herein, we review the recently published finding that cellular prion protein (PrP(c)) is a high-affinity receptor for Abeta oligomers, mediating their toxic effects on synaptic plasticity. We further discuss the relationship between AD and PrP(c) and the potential clinical implications. Cellular prion protein may provide a novel target for therapeutic intervention in AD.

Figure

β-Amyloid (Aβ) oligomer signaling. The amyloid precursor protein (APP) is cleaved by β-secretase and γ-secretase to produce monomeric Aβ peptides that, in turn, assemble into toxic Aβ oligomers. β-Amyloid oligomers bind to cellular prion protein (PrP^c), which likely signals via a putative transmembrane PrP^c coreceptor. This binding mediates the inhibition of synaptic plasticity as measured by long-term potentiation and could be involved in other deleterious effects of Aβ oligomers, including synapse degeneration, rodent spatial memory impairments, and the neurodegeneration seen in human Alzheimer disease. Long-term potentiation may be suppressed by altering neurotransmission through N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors (AMPARs), as their distribution has been shown to be regulated by Aβ oligomers.