Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra

Guanosine triphosphate cyclohydrolase I (GTPCHI) is a critical enzyme in ca techolamine function and is rate limiting for the synthesis of the catechol amine co-factor tetrahydrobiopterin. The present study assessed the distrib ution of GTPCHI immunoreactivity (-ir) within the monkey and human ventral midbrain and determined whether its expression is altered as a function of age. Light and confocal microscopic analyses revealed that young monkeys an d humans displayed GTPCHI-ir within melanin-containing and tyrosine-hydroxy lase-ir neurons in primate substantia nigra. Stereological counts revealed that there was a 67.4% reduction in GTPCHI-ir neuronal number, a 63.5% redu ction in GTPCHI-ir neuronal density, and a 37.6% reduction in neuronal volu me in aged monkeys relative to young cohorts. Similar age-related changes w ere seen in humans, in whom there were significant reductions in the number of GTPCHI-ir nigral neurons in middle age (58.4%) and aged (81.5%) cases r elative to young cohorts. The density of GTPCHI-ir neurons within the nigra was similarly reduced in middle-aged (63.0%) and aged (81.8%) cases. In co ntrast to monkeys, aged humans did not display shrinkage in the volume of G TPCHI-ir nigral neurons. The presence of numerous melanin-positive, but GTP CHI-ir immunonegative, neurons in the aged monkey and human nigra indicates that these decreases represent an age-related phenotypic downregulation of this enzyme and not a loss Of neurons per se. These data indicate that the re is a dramatic decrease in GTPCHI-ir in nonhuman primates and humans as a function of age and that loss of this enzyme may be partly responsible for the age-related decrease in dopaminergic tone within nigrostriatal systems . J. Comp. Neurol. 426:534-548, 2000. (C), 2000 Wiley-Lisp, Inc.