The Prion Protein Ligand, Stress-Inducible Phosphoprotein 1, Regulates Amyloid-beta Oligomer Toxicity

Author(s):Show less -

Ostapchenko, Valeriy G. ^{[1, 2]} ; Beraldo, Flavio H. ^{[1, 2]} ; Mohammad, Amro H. ^{[1, 3]} ; Xie, Yu-Feng ^{[2, 1]} ; Hirata, Pedro H. F. ^{[1, 4, 5]} ; Magalhaes, Ana C. ^{[1, 3]} ; Lamour, Guillaume ^{[6, 7]} ; Li, Hongbin ^[7] ; Maciejewski, Andrzej ^[8] ; Belrose, Jillian C. ^{[1, 3]} ; Teixeira, Bianca L. ^{[4, 5]} ; Fahnestock, Margaret ^[9] ; Ferreira, Sergio T. ^[10] ; Cashman, Neil R. ^[6] ; Hajj, Glaucia N. M. ^{[4, 5]} ; Jackson, Michael F. ^{[2, 1]} ; Choy, Wing-Yiu ^[8] ; MacDonald, John F. ^{[2, 1, 3]} ; Martins, Vilma R. ^{[4, 5]} ; Prado, Vania F. ^{[2, 1, 3]} ; Prado, Marco A. M. ^{[2, 1, 3]}

Affiliation

^[1] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5K8 - Canada

^[2] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5K8 - Canada

^[3] Univ Western Ontario, Dept Anat & Cell Biol, London, ON N6A 5K8 - Canada

^[4] AC Camargo Canc Ctr, Dept Mol & Cell Biol, Int Res Ctr, BR-01508010 Sao Paulo - Brazil

^[5] Natl Inst Translat Neurosci, BR-01508010 Sao Paulo - Brazil

^[6] Univ British Columbia, Brain Res Ctr, Vancouver, BC V6T 1Z4 - Canada

^[7] Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z4 - Canada

^[8] Univ Western Ontario, Dept Biochem, London, ON N6A 5K8 - Canada

^[9] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON L8S 4K1 - Canada

^[10] Univ Fed Rio de Janeiro, Inst Med Biochem, BR-21941590 Rio De Janeiro - Brazil

• Document type: Journal article
• Source: JOURNAL OF NEUROSCIENCE; v. 33, n. 42, p. 16552-16564, OCT 16 2013.
• Web of Science Citations: 36

Abstract

In Alzheimer's disease (AD), soluble amyloid-beta oligomers (A beta Os) trigger neurotoxic signaling, at least partially, via the cellular prion protein (PrPC). However, it is unknown whether other ligands of PrPC can regulate this potentially toxic interaction. Stress-inducible phosphoprotein 1 (STI1), an Hsp90 cochaperone secreted by astrocytes, binds to PrPC in the vicinity of the A beta O binding site to protect neurons against toxic stimuli. Here, we investigated a potential role of STI1 in A beta O toxicity. We confirmed the specific binding of A beta Os and STI1 to the PrP and showed that STI1 efficiently inhibited A beta O binding to PrP in vitro (IC50 of similar to 70 nM) and also decreased A beta O binding to cultured mouse primary hippocampal neurons. Treatment with STI1 prevented A beta O-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 A beta O-induced cell death and could be rescued by treatment with recombinant STI1. Noteworthy, both A beta O binding to PrPC and PrPC-dependent A beta O toxicity were inhibited by TPR2A, the PrPC-interacting domain of STI1. Additionally, PrPC-STI1 engagement activated alpha 7 nicotinic acetylcholine receptors, which participated in neuroprotection against A beta O-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 PrPC ligand STI1 in protecting neurons in AD and suggest a novel pathway that may help to offset A beta O-induced toxicity. (AU)

• FAPESP's process: 09/14027-2 - Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches
• Grantee: Vilma Regina Martins
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/04370-4 - Translational control in the nervous system: tumor mechanisms
• Grantee: Glaucia Noeli Maroso Hajj
• Support Opportunities: Regular Research Grants