Recent research suggests that the toxicity of Aβ oligomers stems from interactions with the cellular prion protein (see ARF related news story). Now, scientists led by Marco Prado, University of Western Ontario, report that a third party breaks up that dangerous liaison. Released by astrocytes, stress-inducible phosphoprotein 1 (STI1) clings to prion receptors and prevents Aβ from damaging neurons, according to the research. Prado told Alzforum he plans to search for small molecules that mimic STI1 and possibly prevent Aβ oligomer toxicity.

STI1 belongs to a group of co-chaperones that help heat shock protein 90 (Hsp90) guide other proteins to fold properly. Because STI1 binds to the same vicinity in cellular prion protein as does Aβ (see Lopes et al., 2005), Prado and colleagues wondered if the co-chaperone could prevent Aβ toxicity.

To find out, first author Valeriy Ostapchenko and colleagues added STI1 to hippocampal neurons that had been treated with synthetic Aβ oligomers (These were created by letting 100 μM Aβ42 sit refrigerated for 24 hours). STI1 prevented oligomers from attaching to the cell surface and protected neurons against Aβ toxicity. While Aβ oligomers caused spine loss in neurons and lowered long-term potentiation in hippocampal slices, STI1 treatment averted both deficits. Endogenous STI1 appeared necessary for neuronal health as well. Mouse neurons lacking one copy of the STI1 gene and producing half the usual amount of STI1 were more sensitive to Aβ toxicity, and died sooner as a result. Treatment with STI1 prevented oligomer-induced cell death in these haploinsufficient animals and in wild-type neurons.

Together, the results suggest that STI1 protects neurons by preventing Aβ oligomers from binding to the prion protein. The co-chaperone either shields prions from Aβ, or changes the conformation of the prion protein so that oligomers will no longer fit the binding pocket, the authors suggested.

However, co-author Vilma Martins, National Institute for Translational Neuroscience, Sāo Paulo, Brazil, and colleagues previously found another explanation for STI1's protective effects based on prion protein forming a complex with the α7 nicotinic acetylcholine receptors (α7nAChR). When STIi binds the complex, calcium streams through the acetylcholine receptor, triggering signaling pathways that guard against apoptosis (see Beraldo et al., 2010). To find out if that explains how STI1 fends off Aβ oligomer toxicity, Ostapchenko repeated some experiments with α7nAChR-negative neurons. In this case, STI failed to ward off Aβ oligomer-induced cell death. “These beneficial effects [of STI1] appear to involve triggering of signaling through nicotinic α7 receptors, rather than just displacing Aβ from the prion protein,” Michael Rowan, Trinity College Dublin, Ireland, wrote to Alzforum in an email (see full comment below).

How do these results relate to in-vivo mouse physiology and to Alzheimer's disease? The researchers looked at STI1 levels in the brains of aged APPswe/PS1dE9 mice and in postmortem tissue from six human patients. Both contained more STI1 than control tissue, which, the authors suggest, might reflect a compensatory response. Though STI1 is insufficient to fully protect against disease at late stages, it might help early on, Prado told Alzforum.

 

While Prado is screening for STI1 mimics as potential therapeutics, he is also testing to ensure they would not be toxic. The researchers have generated cultured neurons and mice that overexpress the co-chaperone. So far, a fivefold increase causes no problems to cultured cells, and neurons resist Aβ toxicity. In-vivo experiments are ongoing.

“Their data confirms previous observations that the interaction of oligomeric Aβ and the prion protein contributes [to] Aβ toxicity,” Hyoung-gon Lee, Case Western Reserve University, Cleveland, Ohio, wrote to Alzforum in an email (see full comment below). “However, the mechanism for the neuroprotective action of STI1 remains to be elucidated,” he added. Lee wondered if STI1 impacts signaling pathways downstream of the Aβ prion protein interaction, such as the activation of Fyn kinase (see ARF related news story).—Gwyneth Dickey Zakaib

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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.

  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.

References

News Citations

  1. Keystone: Partners in Crime—Do Aβ and Prion Protein Pummel Plasticity?
  2. Tracing Aβ’s Toxicity Through Prion Protein, Fyn Kinase

Paper Citations

  1. . Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J Neurosci. 2005 Dec 7;25(49):11330-9. PubMed.
  2. . Role of alpha7 nicotinic acetylcholine receptor in calcium signaling induced by prion protein interaction with stress-inducible protein 1. J Biol Chem. 2010 Nov 19;285(47):36542-50. PubMed.
  3. . Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001 Jun;17(6):157-65. PubMed.

Further Reading

Papers

  1. . Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci. 2010 May 5;30(18):6367-74. PubMed.
  2. . Amyloid-β-induced synapse damage is mediated via cross-linkage of cellular prion proteins. J Biol Chem. 2011 Nov 4;286(44):37955-63. PubMed.
  3. . Cellular prion protein and Alzheimer disease: Link to oligomeric amyloid-β and neuronal cell death. Prion. 2012 Nov 15;7(2) PubMed.
  4. . Dissociating beta-amyloid from alpha 7 nicotinic acetylcholine receptor by a novel therapeutic agent, S 24795, normalizes alpha 7 nicotinic acetylcholine and NMDA receptor function in Alzheimer's disease brain. J Neurosci. 2009 Sep 2;29(35):10961-73. PubMed.

Primary Papers

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