Yan R, Zhang Y, Zhang J, Zhang X, Han Y, Wang M, Wang D, Huang S, Liu W, Shi Q, Dong X, Zou WQ, Li Z, Ma J. Soluble N-terminal region of prion protein causes rapid neurodegeneration in prion disease. Sci Adv. 2025 Aug 8;11(32):eadw6867. Epub 2025 Aug 6 PubMed.

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  1. This report by Yan and colleagues from the laboratory of Jiyan Ma on the neurotoxicity of the soluble N-terminal region of the prion protein (PrP(N)) has intriguing implications for the pathogenesis of Alzheimer's disease. In vitro studies previously had implicated this part of PrP in prionotic cytotoxicity (e.g., Sonati et al., 2013; Wu et al., 2017), but Yan and colleagues now present in vivo evidence that PrP(N), a naturally occurring, unstructured cleavage product of PrP, induces rapid neurodegeneration in murine models of prion disease. In the authors' mechanistic model, the misfolded (and infectious) form of PrP (PrPSc) binds to membrane-bound cellular PrP (PrPC) in a way that frees PrP(N) to activate a neurotoxic signaling cascade via a (yet unknown) molecule on the cell surface. The significance of this finding lies in past observations that the misfolded (and infectious) form of PrP (PrPSc) is not by itself strongly linked to neurodegeneration; rather, PrPSc initiates the disease, but something else is required to harm cells.
     
    In 2011, John Collinge and coworkers proposed a two-stage model of the development of prion disease in which infectivity and toxicity are uncoupled (Sandberg et al., 2011; Sandberg et al., 2014). In the first (clinically silent) stage, PrPSc levels rapidly rise until they reach a plateau that portends a transition to a discernable neurodegenerative stage; this second stage is marked by a switch from the autocatalytic production of PrPSc to the generation of a toxic form of PrP that leads to clinical disease and death. The researchers refer to the hypothetical toxic PrP as PrPL (L for lethal). The findings in this study present compelling in vivo evidence that the elusive PrPL may, in fact, be PrP(N).
     
    If the Ma group's model of cytotoxicity in prion disease holds up, it might suggest a similar mechanism for neurodegeneration in AD. Mathias Jucker's lab has shown that the pathogenesis of AD-like pathology, similar to that of prion disease, progresses in two distinct stages: an initial stage in which Aβ seeds rapidly accumulate in the brain until reaching a plateau, and a second stage in which neurodegeneration becomes prominent (Rother et al., 2022). 
     
    Stephen Strittmatter and colleagues have demonstrated that Aβ oligomers bind with high affinity to membrane-bound PrP, activating effector pathways with deleterious effects (Laurén et al., 2009; Salazar and Strittmatter, 2017). It is thus conceivable that the binding of aberrant Aβ to PrPC, like the binding of PrPSc to PrPC, frees PrP(N) to activate a cytotoxic signaling cascade. In AD, as in prion diseases, cytotoxicity only becomes salient when the concentration of seeding-active pathogenic proteins exceeds a certain threshold.
     
    Whether PrP(N) mediates the cytotoxicity of Aβ remains to be determined, but it would be an interesting coincidence if Alzheimer's disease and prion diseases turn out to share both a mechanism of abnormal protein propagation and PrP(N) as a cytotoxic effector. In any case, these findings collectively argue that the interaction of Aβ with cellular PrP deserves a closer look, particularly with regard to therapeutic targets that might be available relatively early in the Aβ cascade.

    References:

    Sandberg MK, Al-Doujaily H, Sharps B, Clarke AR, Collinge J. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature. 2011 Feb 24;470(7335):540-2. PubMed.

    Wu B, McDonald AJ, Markham K, Rich CB, McHugh KP, Tatzelt J, Colby DW, Millhauser GL, Harris DA. The N-terminus of the prion protein is a toxic effector regulated by the C-terminus. Elife. 2017 May 20;6 PubMed.

    Sandberg MK, Al-Doujaily H, Sharps B, Clarke AR, Collinge J. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature. 2011 Feb 24;470(7335):540-2. PubMed.

    Sandberg MK, Al-Doujaily H, Sharps B, De Oliveira MW, Schmidt C, Richard-Londt A, Lyall S, Linehan JM, Brandner S, Wadsworth JD, Clarke AR, Collinge J. Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked. Nat Commun. 2014 Jul 9;5:4347. PubMed.

    Rother C, Uhlmann RE, Müller SA, Schelle J, Skodras A, Obermüller U, Häsler LM, Lambert M, Baumann F, Xu Y, Bergmann C, Salvadori G, Loos M, Brzak I, Shimshek D, Neumann U, Dominantly Inherited Alzheimer Network, Walker LC, Schultz SA, Chhatwal JP, Kaeser SA, Lichtenthaler SF, Staufenbiel M, Jucker M. Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae. Nat Commun. 2022 Nov 28;13(1):7333. PubMed.

    Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009 Feb 26;457(7233):1128-32. PubMed.

    Salazar SV, Strittmatter SM. Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease. Biochem Biophys Res Commun. 2017 Feb 19;483(4):1143-1147. Epub 2016 Sep 14 PubMed.

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