Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum - Effects of amyloid beta peptide

The biological roles of nitric oxide (NO) and cGMP as inter- and intracellu lar messengers have been intensively investigated during the last decade. N O and cGMP both mediate physiological effects in the cardiovascular, endocr inological, and immunological systems as well as in central nervous system (CNS). In the CNS, activation of the N-methyl-D-aspartic acid (NMDA) type o f glutamatergic receptor induces Ca2+-dependent NOS and NO release, which t hen activates soluble guanylate cyclase for the synthesis of cGMP. Both compounds appear to be important mediators in long-term potentiation a nd long-term depression, and thus may play important roles in the mechanism s of learning and memory. Aging and the accumulation of amyloid beta (A bet a) peptides are important risk factors for the impairment of memory and dev elopment of dementia. In these studies, the mechanism of basal- and NMDA re ceptor-mediated cGMP formation in different parts of adult and aged brains was evaluated. The relative activity of the NO cascade was determined by as say of NOS and guanylate cyclase activities. In addition, the effect of the neurotoxic fragment 25-35 of A beta (A beta) peptide on basal and NMDA rec eptor-mediated NOS activity was investigated. The studies were carried out using slices of hippocampus, brain cortex, and cerebellum from 3- and 28-mo -old rats. Aging coincided with a decrease in the basal level of cGMP as a consequence of a more active degradation of cGMP by a phosphodiesterase in the aged br ain as compared to the adult brain. Moreover, a loss of the NMDA receptor-s timulated enhancement of the cGMP level determined in the presence of cGMP- phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was observed in hippocampus and cerebellum of aged rats. However, this NMDA receptor re sponse was preserved in aged brain cerebral cortex. A significant enhanceme nt of the basal activity of NOS by about 175 and 160% in hippocampus and ce rebellum, respectively, of aged brain may be involved in the alteration of the NMDA receptor response. The neurotoxic fragment of A beta, peptide 25-3 5, decreased significantly the NMDA receptor-mediated calcium, and calmodul in-dependent NO synthesis that may then be responsible for disturbances of the NO and cGMP signaling pathway. We concluded that cGMP-dependent signal transduction in hippocampus and cer ebellum may become insufficient in senescent brain and may have functional consequences in disturbances of learning and memory processes. A beta pepti de accumulated during brain aging and in Alzheimer disease may be an import ant factor in decreasing the NO-dependent signal transduction mediated by N MDA receptors.