. The Prion Protein Ligand, Stress-Inducible Phosphoprotein 1, Regulates Amyloid-β Oligomer Toxicity. J Neurosci. 2013 Oct 16;33(42):16552-64. PubMed.

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  1. The paper represents a significant advance for a number of reasons. It uncovers the ability of a presumed endogenous ligand, STI1, for cellular PrP to displace Aß oligomers from PrP, albeit at a different PrP binding site. Furthermore, STI1 is increased in AD brain, hinting at a possible compensatory mechanism being triggered by Aß. Perhaps most encouraging, exogenously applied STI1 and an STI1 fragment have protective activity against Aß’s deleterious effects. These beneficial effects appear to involve the triggering of signaling reliant on nicotinic alpha7 receptors, rather than just displacing Aß from PrP.

    View all comments by Michael Rowan
  2. This straightforward experimental approach with multiple experimental model systems provides compelling data to support the hypothesis that Aβ toxicity stems from interaction with the cellular prion protein. The major significance of the study seems to be twofold. First, the data confirms previous observations that the interaction of oligomeric Aβ and PrP contributes to Aβ toxicity. This is a point that has been debated and is mired in conflicting observations from different research groups. Second, another well-characterized PrP ligand, STI1, can prevent the interaction between Aβ and PrP, and subsequent neurotoxicity, likely by competing with Aβ for binding to their receptor, PrP. However, the mechanism for the neuroprotective action of STI1 remains to be elucidated. For example, as indicated in the article, STI1 had no effect on Aβ toxicity in α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice, suggesting that direct competition with Aβ for binding to PrP is unlikely the sole mechanism for STI1's neuroprotective activity. It would be interesting to see whether Aβ/PrP interaction is disturbed by STI1 in α7nAChR KO cells, as shown in wild-type cells. In addition, the effect of STI1 on the downstream signal pathways regulated by Aβ/PrP interaction such as Fyn would provide more insightful information for its action mechanism.

    View all comments by Hyoung-gon Lee

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