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

Elham Rezvani Boroujeni,Seyed Masoud Hosseini,Fabrizio Chiti,Giulia Fani,Cristina Cecchi

doi:10.3390/ijms21197273

Elham Rezvani Boroujeni, Seyed Masoud Hosseini + Show 3 more

Open Access

https://doi.org/10.3390/ijms21197273

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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.

Highlights

Alzheimer’s Disease International (ADI) and the American Alzheimer’s Association (AA) have estimated that over than 50 million people are living with dementia, and that Alzheimer’s disease (AD) is the most common cause and may account for 60–70% of dementia cases [1]
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 Reactive Oxygen Species (ROS) generation and cytosolic Ca2+ uptake induced by oligomeric Aβ42 amyloid-derived diffusible ligands (ADDLs) in neuroblastoma SH-SY5Y cells
Dynamic light scattering (DLS) shows that PrP107–120 dissolved in water has a hydrodynamic diameter (Dh) of 2.11 ± 0.68 nm, corresponding to a Rh of 1.05 ± 0.34 nm (Figure 1), which is in good agreement with that estimated theoretically

Summary

Introduction

Alzheimer’s Disease International (ADI) and the American Alzheimer’s Association (AA) have estimated that over than 50 million people are living with dementia, and that Alzheimer’s disease (AD) is the most common cause and may account for 60–70% of dementia cases [1]. Accumulation of senile plaques formed by Aβ is a major histopathological trait of AD, it is widely accepted that soluble Aβ oligomers, forming as intermediate species in the process of neuritic plaque formation or released from the plaques, can effectively play a key role in neuronal dysfunction and impair synaptic structure and function [6,7] It is well-known that such oligomers can inhibit long-term potentiation (LTP)—a correlate of synaptic plasticity [8,9]—as well as activating expression of the complement system [10,11] and general neurotoxic [6,12]. In spite of the large body of evidence that PrPC mediates the aberrant effects of Aβ oligomers, other studies have indicated that it is not a necessary component for the toxicity cascade induced by Aβ oligomers, as

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