Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease

Soluble oligomers of amyloid-beta (Aβo) are implicated by biochemical and genetic evidence as a trigger for Alzheimer's disease (AD) pathophysiology. A key step is Aβo interaction with the neuronal surface to initiate a cascade of altered signal transduction leading to synaptic dysfunction and damage. This review discusses neuronal cell surface molecules with high affinity selectively for oligomeric disease-associated states of Aβ, with a particular focus on the role of cellular prion protein (PrP^C) in this process. Additional receptors may contribute to mediation of Aβo action, but PrP^C appears to play a primary role in a number of systems. The specificity of binding, the genetic necessity in mouse models of disease and downstream signaling pathways are considered. Signal transduction downstream of Aβo complexes with PrP^C involves metabotropic glutamate receptor 5 (mGluR5), Fyn kinase and Pyk2 kinase, with deleterious effects on synaptic transmission and maintenance. Current data support the hypothesis that a substantial portion of Aβo toxicity in AD is mediated after initial interaction with PrP^C on the neuronal surface. As such, the interaction of Aβo with PrP^C is a potential therapeutic intervention site for AD.