title: Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease.
abstract: 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 (PrPC) in this process. Additional receptors may contribute to mediation of Aβo action, but PrPCappears 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 PrPCinvolves 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 PrPCon the neuronal surface. As such, the interaction of Aβo with PrPCis a potential therapeutic intervention site for AD.
authors.affiliation: Cellular Neuroscience, Neurodegeneration & Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Santiago V
authors.initials: SV
authors.lastname: Salazar
authors.affiliation: Cellular Neuroscience, Neurodegeneration & Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT, USA. Electronic address: Stephen.Strittmatter@yale.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D018621:PrPC Proteins / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D018621:PrPC Proteins
keywords: Alzheimer's disease; Cellular prion protein