Soluble beta -Amyloid sub(1-40) Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses

• Published in: The Journal of neuroscience Vol. 25; no. 48; pp. 11061 - 11070
• Main Authors: Roselli, F, Tirard, M, Lu, J, Hutzler, P, Lamberti, P, Livrea, P, Morabito, M, Almeida, OFX
• Format: Journal Article
• Language: English
• Published: 01-11-2005
• ISSN: 0270-6474; 1529-2401

Amyloid- beta (A beta ) 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 beta oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of A beta 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 beta sub(1-40) reduces PSD-95 protein levels in a dose- and time-dependent manner and that the A beta 1 sub(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 beta 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 beta triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.