Inhibition of NMDA Receptor Activation in the Rostral Ventrolateral Medulla by Amyloid- Peptide in Rats

N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are important in regulating sympathetic tone and cardiovascular function in the rostral ventrolateral medulla (RVLM). Amyloid-beta peptide (A beta) is linked to the pathogenesis of Alzheimer's disease (AD). Cerebro- and cardiovascular diseases might be the risk factors for developing AD. The present study examines the acute effects of soluble A beta on the function of NMDA receptors in rats RVLM. We used the magnitude of increases in the blood pressure (pressor responses) induced by microinjection of NMDA into the RVLM as an index of NMDA receptor function in the RVLM. Soluble A beta was applied by intracerebroventricular (ICV) injection. A beta 1-40 at a lower dose (0.2 nmol) caused a slight reduction, and a higher dose (2 nmol) showed a significant decrease in NMDA-induced pressor responses 10 min after administration. ICV injection of A beta 1-42 (2 nmol) did not affect NMDA-induced pressor responses in the RVLM. Co-administration of A beta 1-40 with ifenprodil or memantine blocked the inhibitory effects of A beta 1-40. Immunohistochemistry analysis showed a significant increase in the immunoreactivity of phosphoserine 1480 of GluN2B subunits (pGluN2B-serine1480) in the neuron of the RVLM without significant changes in phosphoserine 896 of GluN1 subunits (pGluN1-serine896), GluN1 and GluN2B, 10 min following A beta 1-40 administration compared with saline. Interestingly, we found a much higher level of A beta 1-40 compared to that of A beta 1-42 in the cerebrospinal fluid (CSF) measured using enzyme-linked immunosorbent assay 10 min following ICV administration of the same dose (2 nmol) of the peptides. In conclusion, the results suggest that ICV A beta 1-40, but not A beta 1-42, produced an inhibitory effect on NMDA receptor function in the RVLM, which might result from changes in pGluN2B-serine1480 (regulated by casein kinase II). The different elimination of the peptides in the CSF might contribute to the differential effects of A beta 1-40 and A beta 1-42 on NMDA receptor function.