Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease

Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

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Accumulation of cellular prion protein within dystrophic neurites of amyloid plaques in the Alzheimer's disease brain

Neuropathology ◽

10.1111/j.1440-1789.2010.01158.x ◽

2010 ◽

Vol 31 (3) ◽

pp. 208-214 ◽

Cited By ~ 9

Author(s):

Reisuke H. Takahashi ◽

Minoru Tobiume ◽

Yuko Sato ◽

Tetsutaro Sata ◽

Gunnar K. Gouras ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prion Protein ◽

Amyloid Plaques ◽

Cellular Prion Protein ◽

Dystrophic Neurites

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Attempt to Untangle the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19103081 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3081 ◽

Cited By ~ 18

Author(s):

Daniela Sarnataro

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipid Membrane ◽

Prion Diseases ◽

Amyloid Β ◽

Phosphatidyl Inositol ◽

Cellular Prion Protein ◽

Endoplasmic Reticulum Quality Control ◽

Endogenous Proteins ◽

Membrane Components

The misfolding and aggregation of proteins is the neuropathological hallmark for numerous diseases including Alzheimer’s disease, Parkinson’s disease, and prion diseases. It is believed that misfolded and abnormal β-sheets forms of wild-type proteins are the vectors of these diseases by acting as seeds for the aggregation of endogenous proteins. Cellular prion protein (PrPC) is a glycosyl-phosphatidyl-inositol (GPI) anchored glycoprotein that is able to misfold to a pathogenic isoform PrPSc, the causative agent of prion diseases which present as sporadic, dominantly inherited and transmissible infectious disorders. Increasing evidence highlights the importance of prion-like seeding as a mechanism for pathological spread in Alzheimer’s disease and Tauopathy, as well as other neurodegenerative disorders. Here, we report the latest findings on the mechanisms controlling protein folding, focusing on the ER (Endoplasmic Reticulum) quality control of GPI-anchored proteins and describe the “prion-like” properties of amyloid-β and tau assemblies. Furthermore, we highlight the importance of pathogenic assemblies interaction with protein and lipid membrane components and their implications in both prion and Alzheimer’s diseases

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Alzheimer's disease, cellular prion protein, and dolphins

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.12.002 ◽

2018 ◽

Vol 14 (2) ◽

pp. 259-260 ◽

Cited By ~ 5

Author(s):

Giovanni Di Guardo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prion Protein ◽

Cellular Prion Protein

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

International Journal of Molecular Sciences ◽

10.3390/ijms21197273 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7273

Author(s):

Elham Rezvani Boroujeni ◽

Seyed Masoud Hosseini ◽

Giulia Fani ◽

Cristina Cecchi ◽

Fabrizio Chiti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Critical Role ◽

Amyloid Β ◽

Cellular Prion Protein ◽

Ros Generation ◽

Aβ Oligomers ◽

Self Recognition ◽

High Affinity Receptor

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.

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