Regulation of NMDA receptor trafficking by amyloid-beta.
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.
Snyder
Eric M
EM
Laboratory for Molecular and Cellular Neuroscience, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA. ericmaltesnyder@gmail.com
Nong
Yi
Y
Almeida
Claudia G
CG
Paul
Surojit
S
Moran
Timothy
T
Choi
Eun Young
EY
Nairn
Angus C
AC
Salter
Michael W
MW
Lombroso
Paul J
PJ
Gouras
Gunnar K
GK
Greengard
Paul
P
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D050882:CREB-Binding Protein; D019703:Calcineurin / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D004553:Electric Conductivity; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C579166:Chrna7 protein, mouse; C409466:NR1 NMDA receptor; D009687:Nuclear Proteins; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D015534:Trans-Activators; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D016202:N-Methylaspartate; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D019703:Calcineurin; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse