. Prion Protein-mediated Toxicity of Amyloid-β Oligomers Requires Lipid Rafts and the Transmembrane LRP1. J Biol Chem. 2013 Mar 29;288(13):8935-51. PubMed.

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  1. We have hypothesized that Aβ oligomer binding to cellular prion protein (PrPC) plays a central role in the pathogenesis of Alzheimer’s disease (AD) (Gimbel et al., 2010; Lauren et al., 2009; Um et al., 2012). Two recent papers, this one together with Fluharty et al., 2013, provide further evidence for a key role of PrPC in Aβ-mediated toxicity.

    Here, Hooper and colleagues show that specific assemblies of Aβ preferentially bind to PrPC, with downstream activation of the Src family kinase Fyn. We recently defined a signaling cascade by which Aβ activates Fyn and the NR2B subunit of the NMDA receptor in a PrPC-dependent fashion (Um et al., 2012). In addition, similar findings were recently reported by Larson et al. (Larson et al., 2012), providing strong converging evidence for a pathologic Aβ-PrPC-Fyn signaling cascade in AD models. PrPC does not cross the plasma membrane, and the putative transmembrane partners mediating the effects of the Aβ-PrPC complex on Fyn have not been identified. Rushworth et al. suggest that LRP1 links Aβ-PrPC to certain signaling events, and it will be important to explore these interesting findings and expand the search for transmembrane co-receptors.

    Harris and colleagues (Fluharty et al., 2013) confirm that the critical PrPC binding sites for Aβ oligomers are within the N-terminal region of PrPC. They further show that addition of the soluble N-terminal fragment sequesters soluble Aβ, and prevents toxicity mediated by Aβ oligomers both in vitro and in vivo. These findings are similar to the long-term potentiation findings reported by Aguzzi and colleagues (Calella et al., 2010) indicating that the soluble N-terminal fragment of PrPC may serve as an anti-Aβ therapeutic.

    Defining the pathologic Aβ signaling cascade remains a major objective in AD research. Following our report (Um et al., 2012), the recent studies confirm a critical pathway by which Aβ activates Fyn kinase in a PrPC-dependent fashion (Larson et al., 2012; Rushworth et al., 2013). Moving forward, it will be important to delineate additional components of the Aβ-PrPC signaling cascade, and, critically, to evaluate this pathway in human disease. Selective targeting of PrPC itself, or the Aβ-PrPC signaling pathway, represent novel and promising therapeutic interventions for AD.

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    . Prion Protein-mediated Toxicity of Amyloid-β Oligomers Requires Lipid Rafts and the Transmembrane LRP1. J Biol Chem. 2013 Mar 29;288(13):8935-51. PubMed.

    . Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci. 2012 Sep;15(9):1227-35. PubMed.