Deficiency of catecholamine syntheses caused by downregulation of phosphorylation of tyrosine hydroxylase in the cerebral cortex of the senescence-accelerated mouse prone 10 strain with aging

The purpose of this study was to elucidate the alteration of catecholamine metabolism and the contribution of catecholamines to the decline of learning and memory in the brain of the senescence-accelerated mouse prone 10 (SAMP10) with aging. Catecholamines and their metabolites in the cerebral cortex were measured by HPLC-ECD. The protein levels of tyrosine hydroxylase (TH) as well as TH phosphorylated at Ser19 or Ser40, dopamine-β-hydroxylase (DβH), and cAMP-dependent protein kinase (PKA) were determined by western blot analysis. Dopamine (DA) and norepinephrine (NE) levels in SAMP10 were significantly lower than those in control animals. However, no significant difference was observed in catecholamine metabolite levels between SAMP10 and control mice. The level of TH phosphorylation at Ser40 in SAMP10 was significantly lower than that in control mice, but no significant difference was observed in the levels of TH, TH phosphorylated at Ser19, or DβH. The amount of PKA, which regulates the phosphorylation of TH at Ser40, was significantly lower in SAMP10 than in control mice. The present study demonstrated that a decline in DA and NE concentrations was observed in the cerebral cortex of SAMP10 with aging, and this decrease of catecholamine levels was caused by impairment of their synthetic pathway. These impairments are considered to be caused by downregulation of TH phosphorylation at Ser40 as a result of PKA deficiency. The present study suggests that the decline of learning and memory abilities of SAMP10 is caused by a decrease in catecholamine synthesis in the cerebral cortex with aging.