Cellular Prion Protein as a Receptor of Toxic Amyloid-β42 Oligomers Is Important for Alzheimer’s Disease

Zhang, Yuan; Zhao, Yanfang; Zhang, Lei; Yu, Wanpeng; Wang, Yu; Chang, Wenguang

doi:10.3389/fncel.2019.00339

Cited by 53 publications

(58 citation statements)

References 67 publications

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“…The significance of PrP C in the pathogenesis of AD stems from its role as a receptor for Aβ oligomers [ 142 , 143 ]. Aβ 1−42 specifically binds PrP C with high affinity in a saturable and reversible manner, and mediates biologically relevant downstream intracellular signaling events including the loss of synaptic function, impaired memory and cognition, and other functional deficits associated with AD [ 144 , 145 ]. Two binding sites of Aβ have been identified on PrP C : residues 95−105 and residues 23−27 [ 143 ] ( Figure 4 ).…”

Section: Methodsmentioning

confidence: 99%

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

Ashok

Singh

Chaudhary

et al. 2020

IJMS

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Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of AD include extracellular accumulation of amyloid β (Aβ) and intracellular deposits of hyper-phosphorylated tau (p-tau). Neuroinflammation and brain iron dyshomeostasis accompany Aβ and p-tau deposits and, together, lead to progressive neuronal death and dementia. The accumulation of Aβ and iron in drusen, the hallmark of AMD, and Aβ and p-tau in retinal ganglion cells (RGC), the main retinal cell type implicated in glaucoma, and accompanying inflammation suggest overlapping pathology. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline. Some are caused by degeneration of the visual cortex, while others are due to RGC loss or AMD-associated retinal degeneration. Here, we review recent information on Aβ, p-tau, chronic inflammation, and iron dyshomeostasis as common pathogenic mechanisms linking the three degenerative conditions, and iron chelation as a common therapeutic option for these disorders. Additionally discussed is the role of prion protein, infamous for prion disorders, in Aβ-mediated toxicity and, paradoxically, in neuroprotection.

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Section: Methodsmentioning

confidence: 99%

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

Ashok

Singh

Chaudhary

et al. 2020

IJMS

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“…The best known example is the PrPc-AβO interaction and the subsequent signalization cascade [115][116][117]. The simplified pathway is the following (Figure 4): AβO binds to PrPc, then stimulates the Proto-oncogene tyrosine-protein kinase Fyn by activating the metabotropic GluR5.…”

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confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

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“…Previous studies have suggested that the cell surface protein PrP C mediates the toxicity of Aβ 42 oligomers by binding to them and affecting synaptic plasticity and other neuronal functions [ 13 , 14 , 15 , 16 , 17 , 18 ], although a general consensus on this point has not yet been found [ 19 , 20 , 21 ]. One PrP C region of the sequence thought to be involved in Aβ 42 binding encompasses approximately residues 95–110 [ 13 , 14 , 33 , 34 , 35 , 37 , 38 , 39 , 40 , 41 , 42 ]. An antibody raised against residues 93–109 of PrP C (anti-PrP C 93–109 GD11) and a synthetic peptide corresponding to residues 98–107 (PrP 98–107 ) were found to inhibit the toxicity of the Aβ 42 ADDLs to organotypic hippocampal slices, whereas a control PrP 213–230 peptide did not have any such effects [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…A large number of data have shown that PrP C has a high binding affinity for Aβ 42 oligomers [ 33 , 34 ]. Even studies showing that PrP C -expressing and PrP C knock-out mice were equally susceptible to Aβ 42 oligomer-induced cognitive impairment recognized that the oligomers interacted with PrP C with high affinity [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Unlike the many reports showing a role of the N -terminal region of PrP C in the binding of Aβ oligomers, none of the studies reported so far have highlighted a role of the region encompassing residues 106–126 in Aβ 42 oligomer binding [ 34 ]. By contrast, this PrP segment was found to be mainly responsible for prion aggregation [ 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

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

Boroujeni

Hosseini

Fani

et al. 2020

IJMS

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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 (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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Cellular Prion Protein as a Receptor of Toxic Amyloid-β42 Oligomers Is Important for Alzheimer’s Disease

Cited by 53 publications

References 67 publications

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

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

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