Soluble Prion peptide 107–120 protects neuroblastoma SH-SY5Y cells against oligomers associated with Alzheimer’s disease

Abstract: Alzheimer’s disease (AD) is the most prevalent form of dementia and soluble amyloid beta (Abeta) oligomers are thought to play a critical role in AD pathogenesis. Cellular prion protein (PrPC) is a high-affinity receptor for Abeta oligomers and mediates some of their toxic effects. The N-terminal region of PrPC can interact with Abeta, particularly the region encompassing residues 95–110. In this study, we identified a soluble and unstructured prion-derived peptide (PrP107–120) that is external to this region of the sequence and was found to successfully reduce the mitochondrial impairment, intracellular ROS generation and cytosolic Ca2+ uptake induced by oligomeric Abeta42 ADDLs in neuroblastoma SH-SY5Y cells. PrP107–120 was also found to rescue SH-SY5Y cells from Abeta42 ADDL internalization. The peptide did not change the structure and aggregation pathway of Abeta42 ADDLs, did not show co-localization with Abeta42 ADDLs in the cells and showed a partial colocalization with the endogenous cellular PrPC. As a sequence region that is not involved in Abeta binding but in PrP self-recognition, the peptide was suggested to protect against the toxicity of Abeta42 oligomers by interfering with cellular PrPC and/or activating a signaling that protected the cells. These results strongly suggest that PrP107–120 has therapeutic potential for AD.