Amyloid-β impairs, and ibuprofen restores, the cGMP pathway, synaptic expression of AMPA receptors and long-term potentiation in the hippocampus.
Amyloid-β (Aβ) rapidly impairs hippocampal long-term potentiation (LTP) and cognitive function in rats. We hypothesized that: a) Aβ-induced impairment of LTP would be due to impairment of the nitric oxide (NO)-cGMP pathway and AMPA receptor translocation; and b) treatment with the anti-inflammatory drug ibuprofen would restore the NO-cGMP pathway and LTP. The aims of this work were to assess whether ibuprofen prevents and/or rescues Aβ-induced LTP impairments in hippocampal slices and to analyze the role of the altered NO-cGMP-protein kinase G pathway and AMPA receptor phosphorylation and synaptic expression in the mechanisms by which Aβ impairs and ibuprofen restores LTP. Aβ impairs tetanus-induced activation of guanylate cyclase and cGMP increase, preventing protein kinase G activation, phosphorylation of GluR1 in Ser845 and AMPA receptors translocation to synaptic membranes, which is responsible for LTP impairment by Aβ. Ibuprofen prevents LTP impairment by Aβ by restoring guanylate cyclase activation and increase in cGMP and, subsequently, activation of protein kinase G, phosphorylation of GluR1 in Ser845 and synaptic expression of AMPA receptors. Restoration of cGMP levels is enough to restore all this process as indicated by the fact that the cGMP analog 8-Br-cGMP also normalizes the function of this pathway and restores LTP in the presence of Aβ. These results indicate that Aβ impairs LTP by impairing the NO-cGMP pathway and that ibuprofen restores LTP by restoring this pathway. These data suggest that restoring cGMP levels may have therapeutic utility to improve cognitive function impaired by Aβ.
Monfort
Pilar
P
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Felipo
Vicente
V
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007052:Ibuprofen / Q000494:pharmacology* / Q000627:therapeutic use; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018091:Receptors, AMPA; D006152:Cyclic GMP; D007052:Ibuprofen