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Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors

You, Haitao ; Tsutsui, Shigeki ; Hameed, Shahid ; Kannanayakal, Thomas J. ; Chen, Lina ; Xia, Peng ; Engbers, Jordan D. T. ; Lipton, Stuart A. ; Stys, Peter K. ; Zamponi, Gerald W.

Proceedings of the National Academy of Sciences - PNAS, 2012-01, Vol.109 (5), p.1737-1742 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors
Autor: You, Haitao ; Tsutsui, Shigeki ; Hameed, Shahid ; Kannanayakal, Thomas J. ; Chen, Lina ; Xia, Peng ; Engbers, Jordan D. T. ; Lipton, Stuart A. ; Stys, Peter K. ; Zamponi, Gerald W.
Assuntos: Alzheimer's disease ; Alzheimers disease ; Amyloid beta-Peptides - toxicity ; Animals ; Antibodies ; beta -Amyloid ; Biological Sciences ; Calcium ; Cells, Cultured ; Central nervous system ; Chelating agents ; Copper ; Copper - metabolism ; cuprizone ; Female ; Glutamic acid receptors ; Glycine ; Hippocampus ; Injuries ; Inurement ; Ions ; Kinetics ; Molecular modelling ; N methyl D aspartate receptors ; N-Methyl-D-aspartic acid receptors ; Neurons ; Neurotoxicity ; Oligomers ; Peptide Fragments - toxicity ; Pregnancy ; Prion protein ; Prions ; PrPC Proteins - metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors ; Receptors, N-Methyl-D-Aspartate - metabolism ; Steady state current
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2012-01, Vol.109 (5), p.1737-1742
Notas: ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
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1H.Y. and S.T. contributed equally to this work.
Author contributions: H.Y., S.T., S.A.L., P.K.S., and G.W.Z. designed research; H.Y., S.T., S.H., T.J.K., L.C., P.X., and J.D.T.E. performed research; H.Y., S.T., T.J.K., P.K.S., and G.W.Z. analyzed data; and S.A.L., P.K.S., and G.W.Z. wrote the paper.
Edited* by Stanley B. Prusiner, University of California, San Francisco, CA, and approved December 21, 2011 (received for review July 5, 2011)
Descrição: 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 (PrPc), a key copper-binding protein in the CNS. Acute ablation of PrPc by enzymatically cleaving its cell-surface GPI anchor yielded similar effects. Biochemical studies and electrophysiological measurements revealed that PrPc interacts with the NMDAR complex in a copper-dependent manner to allosterically reduce glycine affinity for the receptor. Synthetic human Aβ₁₋₄₂ (10 nM-5 μM) produced an identical effect that could be mitigated by addition of excess copper ions or NMDAR blockers. Taken together, Aβ₁₋₄₂, copper chelators, or PrPc 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 PrPc, one that limits excessive NMDAR activity that might otherwise promote neuronal damage. In addition, we provide a unifying molecular mechanism whereby toxic species of Aβ₁₋₄₂ might mediate neuronal and synaptic injury, at least in part, by disrupting the normal copper-mediated, PrPc dependent inhibition of excessive activity of this highly calciumpermeable glutamate receptor.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors

You, Haitao ; Tsutsui, Shigeki ; Hameed, Shahid ; Kannanayakal, Thomas J. ; Chen, Lina ; Xia, Peng ; Engbers, Jordan D. T. ; Lipton, Stuart A. ; Stys, Peter K. ; Zamponi, Gerald W.

United States: National Academy of Sciences

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