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 β (Aβ) oligomers are thought to play a critical role in AD pathogenesis. Cellular prion protein (PrPC) is a high-affinity receptor for Aβ oligomers and mediates some of their toxic effects. The N-terminal region of PrPC can interact with Aβ, 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 Aβ42 ADDLs in neuroblastoma SH-SY5Y cells. PrP107–120 was also found to rescue SH-SY5Y cells from Aβ42 ADDL internalization. The peptide did not change the structure and aggregation pathway of Aβ42 ADDLs, did not show co-localization with Aβ42 ADDLs in the cells and showed a partial colocalization with the endogenous cellular PrPC. 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 Aβ42 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.

Aβ Oligomers Dysregulate Calcium Homeostasis by Mechanosensitive Activation of AMPA and NMDA Receptors

“…Then, Aβ 42 was converted into ADDLs as previously described and immediately diluted in the appropriate medium and added to the SH-SY5Y cell culture media at the concentration of 1 μM. ADDLs were chosen as representative Aβ 42 oligomers because they are widely used and their morphology and purity were routinely verified in our labs. − …”

Protein Oligomerization

“…In their article, Rezvani Boroujeni et al [ 5 ] report that the 107–120 peptide of the cell-membrane prion protein PrP c plays a protective role in neuroblastoma SH-SY5Y cells against the oligomers of the amyloid beta Aβ 42 peptide. These oligomers promote the generation of toxic reactive oxygen species (ROS), as well as the cellular uptake of Ca 2+ , which are both responsible for the onset of Alzheimer’s disease.…”

“…As mentioned at the beginning, it is noteworthy that each one of the eight contributions included in the Special Issue analyzes and highlights different aspects of the “Protein Oligomerization” topic. Two articles directly investigate pathologies related to oligomer-induced amyloidosis [ 5 , 6 ], while three others examine proteins or pathogenic variants involved in neurodegenerative diseases, but not inherently exhibiting amyloidosis [ 8 , 14 , 16 ]. Additionally, one review provides detailed insights into the structural and functional features of the oligomeric family of N-Ribohydrolases [ 11 ], while another review lists and exhaustively describes various approaches and methods useful for modeling and determining the structure of homo-oligomeric proteins in general [ 10 ].…”