Abstract
Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Amyloid beta-Peptides / pharmacology
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Amyloid beta-Peptides / physiology*
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Amyloid beta-Protein Precursor / genetics
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Animals
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CREB-Binding Protein
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Calcineurin / physiology
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Cell Membrane / metabolism
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Cerebral Cortex / metabolism
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Disease Models, Animal
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Electric Conductivity
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Endocytosis / drug effects
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Enzyme Activation / drug effects
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Mice
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N-Methylaspartate / pharmacology
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Neurons / drug effects
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Neurons / metabolism
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Neurons / physiology
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Nuclear Proteins / metabolism
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Peptide Fragments / pharmacology
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Protein Transport / physiology*
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Protein Tyrosine Phosphatases / metabolism
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Protein Tyrosine Phosphatases, Non-Receptor
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Receptors, Nicotinic / physiology
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Signal Transduction / drug effects
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Synapses / metabolism
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Trans-Activators / metabolism
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alpha7 Nicotinic Acetylcholine Receptor
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Chrna7 protein, mouse
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NR1 NMDA receptor
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Nuclear Proteins
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Peptide Fragments
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Receptors, N-Methyl-D-Aspartate
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Receptors, Nicotinic
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Trans-Activators
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alpha7 Nicotinic Acetylcholine Receptor
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amyloid beta-protein (1-42)
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N-Methylaspartate
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CREB-Binding Protein
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Crebbp protein, mouse
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Calcineurin
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Protein Tyrosine Phosphatases
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Protein Tyrosine Phosphatases, Non-Receptor
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Ptpn5 protein, mouse