title: The prion protein ligand, stress-inducible phosphoprotein 1, regulates amyloid-β oligomer toxicity.
abstract: In Alzheimer's disease (AD), soluble amyloid-β oligomers (AβOs) trigger neurotoxic signaling, at least partially, via the cellular prion protein (PrP(C)). However, it is unknown whether other ligands of PrP(C) can regulate this potentially toxic interaction. Stress-inducible phosphoprotein 1 (STI1), an Hsp90 cochaperone secreted by astrocytes, binds to PrP(C) in 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 PrP in vitro (IC50 of ∼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 PrP(C) and PrP(C)-dependent AβO toxicity were inhibited by TPR2A, the PrP(C)-interacting domain of STI1. Additionally, PrP(C)-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 PrP(C) ligand STI1 in protecting neurons in AD and suggest a novel pathway that may help to offset AβO-induced toxicity.
authors.affiliation: Robarts Research Institute, Departments of Physiology and Pharmacology, Anatomy and Cell Biology, and Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5K8, Department of Molecular and Cell Biology, International Research Center, A. C. Camargo Cancer Center and National Institute for Translational Neuroscience, São Paulo, São Paulo, Brazil, 01508-010, Chemistry Department and Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada L8S 4K1, Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil, 21941-590.
authors.forename: Valeriy G
authors.initials: VG
authors.lastname: Ostapchenko
authors.forename: Flavio H
authors.initials: FH
authors.lastname: Beraldo
authors.forename: Amro H
authors.initials: AH
authors.lastname: Mohammad
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Xie
authors.forename: Pedro H F
authors.initials: PH
authors.lastname: Hirata
authors.forename: Ana C
authors.initials: AC
authors.lastname: Magalhaes
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lamour
authors.forename: Hongbin
authors.initials: H
authors.lastname: Li
authors.forename: Andrzej
authors.initials: A
authors.lastname: Maciejewski
authors.forename: Jillian C
authors.initials: JC
authors.lastname: Belrose
authors.forename: Bianca L
authors.initials: BL
authors.lastname: Teixeira
authors.forename: Margaret
authors.initials: M
authors.lastname: Fahnestock
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
authors.forename: Neil R
authors.initials: NR
authors.lastname: Cashman
authors.forename: Glaucia N M
authors.initials: GN
authors.lastname: Hajj
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jackson
authors.forename: Wing-Yiu
authors.initials: WY
authors.lastname: Choy
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
authors.forename: Vilma R
authors.initials: VR
authors.lastname: Martins
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006360:Heat-Shock Proteins; D018621:PrPC Proteins; C489791:Stip1 protein, mouse; D064569:alpha7 Nicotinic Acetylcholine Receptor