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

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 solubleA oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role ofA 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 A1– 40 reduces PSD-95 protein levels in a dose- and time-dependent manner and that theA11– 40-dependent decrease in PSD-95 requiresNMDARactivity.Wealso 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 theAMPARglutamate 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.