The P’s and Q’s of cellular PrP-Aβ interactions

Westaway, David; Jhamandas, Jack H.

doi:10.4161/pri.20675

Cited by 9 publications

(11 citation statements)

References 59 publications

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“…Aβ42 oligomers were previously shown to interact with PrP C with high-affinity and this complex was recently shown to utilize mGluR5a as a scaffold to facilitate Aβ42 oligomer-dependent intracellular signaling [ 9 , 41 , 42 ]. Moreover, Aβ42 oligomers were shown to stimulate the subcellular redistribution of CaMKII resulting in impaired α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking [ 43 ].…”

Section: Resultsmentioning

confidence: 99%

Ca2+/Calmodulin-dependent protein Kinase II interacts with group I Metabotropic Glutamate and facilitates Receptor Endocytosis and ERK1/2 signaling: role of β-Amyloid

et al. 2015

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BackgroundAgonist stimulation of Group I metabotropic glutamate receptors (mGluRs) initiates their coupling to the heterotrimeric G protein, Gαq/11, resulting in the activation of phospholipase C, the release of Ca2+ from intracellular stores and the subsequent activation of protein kinase C. However, it is now recognized that mGluR5a also functions as a receptor for cellular prion protein (PrPC) and β-amyloid peptide (Aβ42) oligomers to facilitate intracellular signaling via the resulting protein complex. Intracellular mGluR5a signaling is also regulated by its association with a wide variety of intracellular regulation proteins.ResultsIn the present study, we utilized mass spectroscopy to identify calmodulin kinase IIα (CaMKIIα) as a protein that interacts with the second intracellular loop domain of mGluR5. We show that CaMKIIα interacts with both mGluR1a and mGluR5a in an agonist-independent manner and is co-immunoprecipitated with mGluR5a from hippocampal mouse brain. CaMKIIα positively regulates both mGluR1a and mGluR5a endocytosis, but selectively attenuates mGluR5a but not mGluR1a-stimulated ERK1/2 phosphorylation in a kinase activity-dependent manner. We also find that Aβ42 oligomers stimulate the association of CaMKIIα with mGluR5a and activate ERK1/2 in an mGluR5a-dependent manner. However, Aβ42 oligomer-stimulated ERK1/2 phosphorylation is not regulated by mGluR5a/CaMKIIα interactions suggesting that agonist and Aβ42 oligomers stabilize distinct mGluR5a activation states that are differentially regulated by CaMKIIα. The expression of both mGluR5a and PrPC together, but not alone resulted in the agonist-stimulated subcellular distribution of CaMKIIα into cytoplasmic puncta.ConclusionsTaken together these results indicate that CaMKIIα selectively regulates mGluR1a and mGluR5a ERK1/2 signaling. As mGluR5 and CaMKIIα are involved in learning and memory and Aβ and mGluR5 are implicated in Alzheimer’s disease, results of these studies could provide insight into potential pharmacological targets for treatment of Alzheimer’s disease.

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Section: Resultsmentioning

confidence: 99%

Ca2+/Calmodulin-dependent protein Kinase II interacts with group I Metabotropic Glutamate and facilitates Receptor Endocytosis and ERK1/2 signaling: role of β-Amyloid

et al. 2015

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“…PrP interaction with Aβ has received a lot of attention because of the propensity of PrP to induce neurodegeneration and associated memory-like dysfunction [201] . It has been proposed that cell surface PrP can act as a receptor for Aβ [202] .…”

Section: Cross-interactions Of App and App Metabolites With Receptor-mentioning

confidence: 99%

APP Receptor? To Be or Not To Be

Deyts

Wang

Parent

2016

Trends in Pharmacological Sciences

112

110

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Amyloid Precursor Protein (APP) and its metabolites play a critical role in Alzheimer’s disease pathogenesis. The idea that APP may function as a receptor has gained momentum based on its structural similarities to type I transmembrane receptors, and the identification of putative APP ligands. Here we review the recent experimental evidence in support of this notion and discuss how this concept is viewed in the field. Specifically, we focus on the structural and functional characteristics of APP as a cell surface receptor, and its interaction with adaptors and signaling proteins. We also address the importance of APP's function as a receptor in Alzheimer’s disease etiology and discuss how this function might be potentially important for the development of novel therapeutic approaches.

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“…As recently pointed out by Westaway and Jhamandas (2012) 76 taking in account of the potential negative synergistic effect of Aβ oligomers-PrP C , there is also ample data in favor of a neuroprotective effect of PrP C . [77][78][79][80] Rial et al (2012) 81 showed that the overepression of PrP C in transgenic mice prevented cognitive dysfunction and the apoptotic neuronal cell death induced by Aβ1-40.…”

Section: Discussionmentioning

confidence: 97%

The neurodegeneration in Alzheimer disease and the prion protein

Forloni

Sclip

Borsello

et al. 2013

Prion

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The concept of "prion-like" has been proposed to explain the pathogenic mechanism of the principal neurodegenerative disorders associated with protein misfolding, including Alzheimer disease (AD). Other evidence relates prion protein with AD: the cellular prion protein (PrP(C)) binds β amyloid oligomers, allegedly responsible for the neurodegeneration in AD, mediating their toxic effects. We and others have confirmed the high-affinity binding between β amyloid oligomers and PrP(C), but we were not able to assess the functional consequences of this interaction using behavioral investigations and in vitro tests. This discrepancy rather than being resolved with the classic explanations, differencies in methodological aspects, has been reinforced by new data from different sources. Here we present data obtained with PrP antibody that not interfere with the neurotoxic activity of β amyloid oligomers. Since the potential role of the PrP(C) in the neuronal dysfunction induced by β amyloid oligomers is an important issue, find reasonable explanation of the inconsistent results is needed. Even more important however is the relevance of this interaction in the context of the disease, so as to develop valid therapeutic strategies.

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The P’s and Q’s of cellular PrP-Aβ interactions

Cited by 9 publications

References 59 publications

Ca2+/Calmodulin-dependent protein Kinase II interacts with group I Metabotropic Glutamate and facilitates Receptor Endocytosis and ERK1/2 signaling: role of β-Amyloid

Ca2+/Calmodulin-dependent protein Kinase II interacts with group I Metabotropic Glutamate and facilitates Receptor Endocytosis and ERK1/2 signaling: role of β-Amyloid

APP Receptor? To Be or Not To Be

The neurodegeneration in Alzheimer disease and the prion protein

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