| First Author | Ostapchenko VG | Year | 2013 |
| Journal | J Neurosci | Volume | 33 |
| Issue | 42 | Pages | 16552-64 |
| PubMed ID | 24133259 | Mgi Jnum | J:202745 |
| Mgi Id | MGI:5521405 | Doi | 10.1523/JNEUROSCI.3214-13.2013 |
| Citation | Ostapchenko VG, et al. (2013) The prion protein ligand, stress-inducible phosphoprotein 1, regulates amyloid-beta oligomer toxicity. J Neurosci 33(42):16552-64 |
| abstractText | In Alzheimer's disease (AD), soluble amyloid-beta oligomers (AbetaOs) 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 AbetaO binding site to protect neurons against toxic stimuli. Here, we investigated a potential role of STI1 in AbetaO toxicity. We confirmed the specific binding of AbetaOs and STI1 to the PrP and showed that STI1 efficiently inhibited AbetaO binding to PrP in vitro (IC50 of approximately 70 nm) and also decreased AbetaO binding to cultured mouse primary hippocampal neurons. Treatment with STI1 prevented AbetaO-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 AbetaO-induced cell death and could be rescued by treatment with recombinant STI1. Noteworthy, both AbetaO binding to PrP(C) and PrP(C)-dependent AbetaO toxicity were inhibited by TPR2A, the PrP(C)-interacting domain of STI1. Additionally, PrP(C)-STI1 engagement activated alpha7 nicotinic acetylcholine receptors, which participated in neuroprotection against AbetaO-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 AbetaO-induced toxicity. |
