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(C)) is a high-affinity receptor for Aβ oligomers and mediates some of their toxic effects. The N-terminal region of PrP(C) can interact with Aβ, particularly the region encompassing residues 95–110. In this study, we identified a soluble and unstructured prion-derived peptide (PrP(107–120)) that is external to this region of the sequence and was found to successfully reduce the mitochondrial impairment, intracellular ROS generation and cytosolic Ca(2+) uptake induced by oligomeric Aβ(42) ADDLs in neuroblastoma SH-SY5Y cells. PrP(107–120) was also found to rescue SH-SY5Y cells from Aβ(42) ADDL internalization. The peptide did not change the structure and aggregation pathway of Aβ(42) ADDLs, did not show co-localization with Aβ(42) ADDLs in the cells and showed a partial colocalization with the endogenous cellular PrP(C). 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(42) oligomers by interfering with cellular PrP(C) and/or activating a signaling that protected the cells. These results strongly suggest that PrP(107–120) has therapeutic potential for AD.