Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses.
Amyloid-beta (Abeta) has been implicated in memory loss and disruption of synaptic plasticity observed in early-stage Alzheimer's disease. Recently, it has been shown that soluble Abeta oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of Abeta in the regulation of synaptic structure and function. Postsynaptic density-95 (PSD-95) is a postsynaptic scaffolding protein that plays a critical role in synaptic plasticity and the stabilization of AMPA (AMPARs) and NMDA (NMDARs) receptors at synapses. Here, we show that exposure of cultured cortical neurons to soluble oligomers of Abeta(1-40) reduces PSD-95 protein levels in a dose- and time-dependent manner and that the Abeta1(1-40)-dependent decrease in PSD-95 requires NMDAR activity. We also show that the decrease in PSD-95 requires cyclin-dependent kinase 5 activity and involves the proteasome pathway. Immunostaining analysis of cortical cultured neurons revealed that Abeta treatment induces concomitant decreases in PSD-95 at synapses and in the surface expression of the AMPAR glutamate receptor subunit 2. Together, these data suggest a novel pathway by which Abeta triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.
Roselli
F
F
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Tirard
M
M
Lu
J
J
Hutzler
P
P
Lamberti
P
P
Livrea
P
P
Morabito
M
M
Almeida
O F X
OF
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D015536:Down-Regulation; D005625:Frontal Lobe / Q000166:cytology / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012995:Solubility; D013569:Synapses / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C078592:amyloid beta-protein (1-40); D018698:Glutamic Acid; D016202:N-Methylaspartate; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D046988:Proteasome Endopeptidase Complex; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium