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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 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 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 PrPC and PrPC-dependent AβO toxicity were inhibited by TPR2A, the PrPC-interacting domain of STI1. Additionally, PrPC-STI1 engagement activatedα7 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 PrPC ligand STI1 in protecting neurons in AD and suggest a novel pathway that may help to offset AβO-induced toxicity. [ABSTRACT FROM AUTHOR]

In Alzheimer’s disease, the amyloid-b peptide (Ab) interacts with distinct proteins at the cell surface to interfere with synaptic communication. Recent data have implicated the prion protein (PrPC) as a putative receptor for Ab. We show here that Ab oligomers signal in cells in a PrPC-dependent manner, as might be expected if Ab oligomers use PrPC as a receptor. Immunofluorescence, flow cytometry and cell surface protein biotinylation experiments indicated that treatment with Ab oligomers, but not monomers, increased the localization of PrPC at the cell surface in cell lines. These results were reproduced in hippocampal neuronal cultures by labeling cell surface PrPC. In order to understand possible mechanisms involved with this effect of Ab oligomers, we used live cell confocal and total internal reflection microscopy in cell lines. Ab oligomers inhibited the constitutive endocytosis of PrPC, but we also found that after Ab oligomer- treatment PrPC formed more clusters at the cell surface, suggesting the possibility of multiple effects of Ab oligomers. Our experiments show for the first time that Ab oligomers signal in a PrPC-dependent way and that they can affect PrPC trafficking, increasing its localization at the cell surface. [ABSTRACT FROM AUTHOR]