NMDA receptors and BAX are essential for Ab impairment of LTP

Accumulation of amyloid-beta (A beta) is a hallmark of Alzheimer's disease, a neurodegenerative disorder in which synapse loss and dysfunction are early features. Acute exposure of hippocampal slices to Ab leads to changes in synaptic plasticity, specifically reduced long-term potentiation (LTP) and enhanced long-term depression (LTD), with no change in basal synaptic transmission. We also report here that D-AP5, a non-selective NMDA receptor antagonist, completely prevented A beta-mediated inhibition of LTP in area CA1 of the hippocampus. Ro25-6981, an antagonist selective for GluN2B (NR2B) NMDA receptors, only partially prevented this A beta action, suggesting that GluN2A and GluN2B receptors may both contribute to A beta suppression of LTP. The effect of A beta on LTP was also examined in hippocampal slices from BAX -/- mice and wild-type littermates. A beta failed to block LTP in hippocampal slices from BAX -/- mice, indicating that BAX is essential for A beta inhibition of LTP.