Amyloid-β induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease

Abstract

Alzheimer disease (AD) is the most prevalent cause of dementia. Amyloid-β (Aβ) oligomers are potent synaptotoxins thought to mediate AD-related phenotypes. Cellular prion protein (PrP(C)) has been identified as a high-affinity receptor for Aβ oligomers. Herein, we review the functional consequences of Aβ oligomer binding to PrP(C) on the neuronal surface. We highlight recent evidence that Fyn kinase mediates signal transduction downstream of the PrP(C)-Aβ oligomer complex. These studies suggest that PrP(C) has a central role in AD pathogenesis and may provide a target for therapeutic intervention in AD.

Keywords: Alzheimer disease; Fyn kinase; PrpC; cellular prion protein; prion.

Figure 1. Molecular model for Aβ oligomer induced synaptic dysfunction. The amyloid precursor protein (APP) is processed by β- and γ-secretase to yield Aβ monomer. The Aβ monomer can undergo a conformational change coincident with assembly into toxic oligomers. Aβ oligomer binding to cellular prion protein (PrP^C) at the neuronal post-synaptic density activates Fyn tyrosine kinase. PrP^C may couple to Fyn through an as yet unidentified transmembrane protein. Aβ oligomer stimulation of Fyn signaling drives the tyrosine phosphorylation of the NR2B subunit of NMDA receptors. NMDA receptor phosphorylation in turn produces altered surface expression, dysregulation of receptor function, excitoxicity and dendritic spine retraction.