Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss

摘要

Synaptic loss is one of the major features of Alzheimer’s disease (AD) and correlates with the degree of dementia. N -methyl- d -aspartate receptors (NMDARs) have been shown to mediate downstream effects of the β -amyloid peptide (A β ) in AD models. NMDARs can trigger intracellular cascades via Ca2+ entry, however, also Ca2+-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by A β . We show that endogenous A β as well as exogenously added synthetic A β oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca2+ chelator BAPTA or open-channel blockers MK-801 or memantine. A β increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. A β -induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca2+ flux for synaptic degeneration by A β . We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of A β oligomers. Our data suggest that A β induces the activation of p38 MAPK and subsequent synaptic loss through Ca2+ flux- and G protein-independent mechanisms.