Soluble β-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses

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(1 -40) reduces PSD-95 protein levels in a dose- and time- dependent manner and that the A beta 1(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.