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The Journal of Neuroscience, November 30, 2005, 25(48):11061-11070; doi:10.1523/JNEUROSCI.3034-05.2005

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Neurobiology of Disease
Soluble -Amyloid_1-40 Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses

F. Roselli,^1,2 M. Tirard,¹ J. Lu,¹ P. Hutzler,³ P. Lamberti,² P. Livrea,² M. Morabito,⁴ and O. F. X. Almeida¹

¹Max Planck Institute of Psychiatry, 80804 Munich, Germany, ²Department of Neurological and Psychiatric Sciences, University of Bari, 70124 Bari, Italy, ³Institute of Pathology, GSF National Research Center for Environment and Health, 85764 Neuherberg, Germany, and ⁴Department of Cell Biology, University of Massachusetts Medical School, E. K. Shriver Center, Waltham, Massachusetts 02452

Amyloid- (A) 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 A oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of A 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 A_1-40 reduces PSD-95 protein levels in a dose- and time-dependent manner and that the A1_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 A 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 A triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.

Key words: phosphorylation; glutamate receptor; metabotropic glutamate receptor; AMPA receptor; synaptic plasticity; amyloid ; A peptide; NMDA receptor; PSD-95; proteasome; cdk5

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Received July 22, 2005; revised October 4, 2005; accepted October 15, 2005.

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