Potentiation of NMDA-Mediated Responses by Amyloid-β Peptide 1-40 in Rat Sympathetic Preganglionic Neurons

The abnormal accumulation of amyloid-beta peptides (A beta) is one of the main characteristics of Alzheimer's disease (AD). Cerebro- and cardiovascular diseases may be the risk factors for developing AD. The effect of A beta on central sympathetic control of cardiovascular function remains unclear. The present study examines the acute effects of A beta oligomers on the function of NMDA receptors, a subtype of ionotropic glutamate receptors, in rat sympathetic preganglionic neurons (SPNs). In the in vitro electrophysiological study, A beta(1-40) but not A beta(1-42) applied by superfusion for 5 min significantly potentiated NMDA-induced depolarizations in SPNs of neonatal rat spinal cord slice preparation. Application of A beta(1-40) had little effects on AMPA-induced depolarizations or GABA-induced hyperpolarizations. Treatment with a selective protein kinase C (PKC) inhibitor applied together with A beta(1-40) blocked the augmentation by A beta(1-40) of NMDA-induced depolarizations. Western blot analysis showed an increase in the levels of phosphoserine 896, selectively regulated by PKC, without significant changes in phosphoserine 897 on GluN1 subunits in lateral horn areas of spinal cord slices following treatment with A beta(1-40). In the in vivo study, intrathecal injection of A beta(1-40) (0.2 nmol) potentiated the pressor effects induced by NMDA (2 nmol) injected intrathecally in urethane-anesthetized rats. These results suggest that different fragments of A beta may have differential effects on the NMDA receptor function and the selective augmentation of NMDA receptor function by A beta(1-40) may involve PKC-dependent mechanisms in sympathetic preganglionic neurons.