Age and region-specific responses of microglia, but not astrocytes, suggest a role in selective vulnerability of dopamine neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure in monkeys.

Little is known about the effects of aging, the strongest risk factor for Parkinson's disease (PD), on glial responses to dopamine (DA) neuron degeneration in midbrain subregions that display selective vulnerability to degeneration. We evaluated the impact of aging on astrocytes and microglia in a regionally specific manner in a monkey model of PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was delivered unilaterally via the internal carotid artery of young, middle-aged, and old-aged rhesus monkeys. Astrocytes and microglia were identified using glial fibrillary acidic protein and human leukocyte antigen-DR (HLA-DR) immunolabeling, respectively. Glial reactivity was assessed using (1) stereological cell counting, (2) fluorescence intensity, and (3) a morphology rating scale. In the midbrain contralateral and ipsilateral to the MPTP injection, astrocyte number and intensity did not change with age. In both sides of the midbrain, cellular morphology suggested astrocyte hypertrophy in middle-age dissipated in old-age, irrespective of DA subregion and regional differences in vulnerability to degeneration. In the contralateral midbrain, microglia became mildly activated (increased cell number and intensity, and morphological changes) with advancing age. Inflammation was evident at 3 months postlesion by severe microglial activation in the ipsilateral midbrain. HLA-DR fluorescence intensity and an abundance of activated microglia (based on morphological criteria) were consistently exacerbated in the vtSN of both sides of the midbrain. These results suggest the glial responses accompanying aging and DA neuron degeneration following a toxic insult represent persistent alterations in the microenvironment of surviving DA neurons that are important factors in understanding regional differences in susceptibility to degeneration.