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 catecholamine function and is rate limiting for the synthesis of the catecholamine co‐factor tetrahydrobiopterin. The present study assessed the distribution 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 and humans displayed GTPCHI‐ir within melanin‐containing and tyrosine‐hydroxylase‐ir neurons in primate substantia nigra. Stereological counts revealed that there was a 67.4% reduction in GTPCHI‐ir neuronal number, a 63.5% reduction in GTPCHI‐ir neuronal density, and a 37.6% reduction in neuronal volume in aged monkeys relative to young cohorts. Similar age‐related changes were 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 relative 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 contrast to monkeys, aged humans did not display shrinkage in the volume of GTPCHI‐ir nigral neurons. The presence of numerous melanin‐positive, but GTPCHI‐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 there 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. © 2000 Wiley‐Liss, Inc.