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
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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.
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