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

Author:
Salazar, Santiago V., Strittmatter, Stephen M.
Source:
Biochemical and biophysical research communications 2017 v.483 pp. 1143-1147
ISSN:
0006-291X
Subject:
Alzheimer disease, animal models, disease models, glutamate receptors, neurons, pathophysiology, prions, signal transduction, synaptic transmission, toxicity
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 PrPC 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 PrPC 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 PrPC on the neuronal surface. As such, the interaction of Aβo with PrPC is a potential therapeutic intervention site for AD.
Agid:
5563652