ArticleProceedings of the National Academy of Sciences of the United States of America2012
Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers.
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Who cites it
123 citing papers in PubMed, 237 citations in OpenAlex.
- A primer on copper biology in the brain.Neurobiology of disease · 2025Review
- Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice.The Journal of clinical investigation · 2025Article
- Familial Alzheimer's disease mutations in amyloid precursor protein impair calcineurin signaling to NMDA receptors.The Journal of biological chemistry · 2025Article
- A Copper-Binding Peptide with Therapeutic Potential against Alzheimer's Disease: From the Blood-Brain Barrier to Metal Competition.ACS chemical neuroscience · 2025Article
- Fyn Kinase in Alzheimer's Disease: Unraveling Molecular Mechanisms and Therapeutic Implications.Molecular neurobiology · 2025Review
- Comparing Prion Proteins Across Species: Is Zebrafish a Useful Model?Molecular neurobiology · 2025Review
- The physiological and pathophysiological roles of copper in the nervous system.The European journal of neuroscience · 2024Review
- Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.International journal of molecular sciences · 2024Review
- Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology.EMBO reports · 2024Article
- The underlying molecular mechanisms of Fyn in neonatal hypoxic-ischaemic encephalopathy.Frontiers in cellular neuroscience · 2024Review
- An LRP1-binding motif in cellular prion protein replicates cell-signaling activities of the full-length protein.JCI insight · 2023Article
- Imaging Amyloid-β Membrane Interactions: Ion-Channel Pores and Lipid-Bilayer Permeability in Alzheimer's Disease.Angewandte Chemie (International ed. in English) · 2023Review
- Imaging Amyloid-β Membrane Interactions: Ion-Channel Pores and Lipid-Bilayer Permeability in Alzheimer's Disease.Angewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2023Review
- Metals in Alzheimer's Disease.Biomedicines · 2023Review
- Mechanisms of prion-induced toxicity.Cell and tissue research · 2023Review
- Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein.Cell and tissue research · 2023Review
- The LRP1/CD91 ligands, tissue-type plasminogen activator, αScientific reports · 2022Article
- Prions induce an early Arc response and a subsequent reduction in mGluR5 in the hippocampus.Neurobiology of disease · 2022Article
- Structural and dynamical determinants of a β-sheet-enriched intermediate involved in amyloid fibrillar assembly of human prion protein.Chemical science · 2022Article
- Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner.Molecular brain · 2022Article
63 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
N-methyl-d-aspartate receptors (NMDARs) mediate critical CNS functions, whereas excessive activity contributes to neuronal damage. At physiological glycine concentrations, NMDAR currents recorded from cultured rodent hippocampal neurons exhibited strong desensitization in the continued presence of NMDA, thus protecting neurons from calcium overload. Reducing copper availability by specific chelators (bathocuproine disulfonate, cuprizone) induced nondesensitizing NMDAR currents even at physiologically low glycine concentrations. This effect was mimicked by, and was not additive with, genetic ablation of cellular prion protein (PrP(C)), a key copper-binding protein in the CNS. Acute ablation of PrP(C) by enzymatically cleaving its cell-surface GPI anchor yielded similar effects. Biochemical studies and electrophysiological measurements revealed that PrP(C) interacts with the NMDAR complex in a copper-dependent manner to allosterically reduce glycine affinity for the receptor. Synthetic human Aβ(1-42) (10 nM-5 μM) produced an identical effect that could be mitigated by addition of excess copper ions or NMDAR blockers. Taken together, Aβ(1-42), copper chelators, or PrP(C) inactivation all enhance the activity of glycine at the NMDAR, giving rise to pathologically large nondesensitizing steady-state NMDAR currents and neurotoxicity. We propose a physiological role for PrP(C), one that limits excessive NMDAR activity that might otherwise promote neuronal damage. In addition, we provide a unifying molecular mechanism whereby toxic species of Aβ(1-42) might mediate neuronal and synaptic injury, at least in part, by disrupting the normal copper-mediated, PrP(C)-dependent inhibition of excessive activity of this highly calcium-permeable glutamate receptor.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.