The Prion Protein Ligand, Stress-Inducible Phosphoprotein 1, Regulates Amyloid-β Oligomer Toxicity Journal Articles uri icon

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  • In Alzheimer's disease (AD), soluble amyloid-β oligomers (AβOs) trigger neurotoxic signaling, at least partially, via the cellular prion protein (PrPC). However, it is unknown whether other ligands of PrPCcan regulate this potentially toxic interaction. Stress-inducible phosphoprotein 1 (STI1), an Hsp90 cochaperone secreted by astrocytes, binds to PrPCin the vicinity of the AβO binding site to protect neurons against toxic stimuli. Here, we investigated a potential role of STI1 in AβO toxicity. We confirmed the specific binding of AβOs and STI1 to the PrP and showed that STI1 efficiently inhibited AβO binding to PrPin vitro(IC50of ∼70 nm) and also decreased AβO binding to cultured mouse primary hippocampal neurons. Treatment with STI1 prevented AβO-induced synaptic loss and neuronal death in mouse cultured neurons and long-term potentiation inhibition in mouse hippocampal slices. Interestingly, STI1-haploinsufficient neurons were more sensitive to AβO-induced cell death and could be rescued by treatment with recombinant STI1. Noteworthy, both AβO binding to PrPCand PrPC-dependent AβO toxicity were inhibited by TPR2A, the PrPC-interacting domain of STI1. Additionally, PrPC–STI1 engagement activated α7 nicotinic acetylcholine receptors, which participated in neuroprotection against AβO-induced toxicity. We found an age-dependent upregulation of cortical STI1 in the APPswe/PS1dE9 mouse model of AD and in the brains of AD-affected individuals, suggesting a compensatory response. Our findings reveal a previously unrecognized role of the PrPCligand STI1 in protecting neurons in AD and suggest a novel pathway that may help to offset AβO-induced toxicity.


  • Ostapchenko, Valeriy G
  • Beraldo, Flavio H
  • Mohammad, Amro H
  • Xie, Yu-Feng
  • Hirata, Pedro HF
  • Magalhaes, Ana C
  • Lamour, Guillaume
  • Li, Hongbin
  • Maciejewski, Andrzej
  • Belrose, Jillian C
  • Teixeira, Bianca L
  • Fahnestock, Margaret
  • Ferreira, Sergio T
  • Cashman, Neil R
  • Hajj, Glaucia NM
  • Jackson, Michael F
  • Choy, Wing-Yiu
  • MacDonald, John F
  • Martins, Vilma R
  • Prado, Vania F
  • Prado, Marco AM

publication date

  • October 16, 2013