Soluble Prion Peptide 107-120 Protects Neuroblastoma SH-SY5Y Cells against Oligomers Associated with Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent form of dementia and soluble amyloid β (Aβ) oligomers are thought to play a critical role in AD pathogenesis. Cellular prion protein (PrP) is a high-affinity receptor for Aβ oligomers and mediates some of their toxic effects. The -terminal region of PrP can interact with Aβ, particularly the region encompassing residues 95-110. In this study, we identified a soluble and unstructured prion-derived peptide (PrP) that is external to this region of the sequence and was found to successfully reduce the mitochondrial impairment, intracellular ROS generation and cytosolic Ca uptake induced by oligomeric Aβ ADDLs in neuroblastoma SH-SY5Y cells. PrP was also found to rescue SH-SY5Y cells from Aβ ADDL internalization. The peptide did not change the structure and aggregation pathway of Aβ ADDLs, did not show co-localization with Aβ ADDLs in the cells and showed a partial colocalization with the endogenous cellular PrP. As a sequence region that is not involved in Aβ binding but in PrP self-recognition, the peptide was suggested to protect against the toxicity of Aβ oligomers by interfering with cellular PrP and/or activating a signaling that protected the cells. These results strongly suggest that PrP has therapeutic potential for AD.