Aging of the nigrostriatal system in the squirrel monkey

Abstract

Increasing incidence of Parkinson's disease with advancing age suggests that age-related processes predispose the nigrostriatal dopaminergic system to neurodegeneration. Several hypotheses concerning the effects of aging on nigrostriatal neurons were assessed in this study using a non-human primate model. First, we examined the possibility that the total number of dopaminergic neurons decline in the substantia nigra as a function of age. Stereological counting based on both tyrosine hydroxylase immunoreactivity (TH-ir) and neuromelanin (NM) content revealed no difference in cell number between young, middle-aged and old squirrel monkeys. We then determined whether advancing age changed the relative proportion of neurons characterized by 1) TH-ir in the absence of NM, 2) the presence of both TH-ir and NM, or 3) NM without TH-ir. Indeed, a progressive age-related depletion of TH only cells was paralleled by an increase in NM only neurons. The possibility that these changes could underlie a functional impairment of the nigrostriatal system was supported by striatal dopamine measurements showing a decrease in older monkeys. Finally, we tested the hypotheses that aging may enhance cell vulnerability to injury and that different dopaminergic subpopulations display varying degrees of susceptibility. When monkeys were exposed to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, cell loss was markedly more pronounced in older animals, and the ranking of vulnerability was TH only < TH/NM < NM only cells. The data indicate that, even in the absence of an overall neuronal loss, changes in the characteristics of dopaminergic cells reflect functional deficits and increased vulnerability to injury with age. NM content appears to be an important marker of these age-related effects.

Nicotinic receptors as CNS targets for Parkinson's disease

“…This possibility is consistent with previous work indicating that dopaminergic afferents from the nigra to the striatum are variably susceptible to nigrostriatal insults [114,115]. Studies to understand the molecular basis for this enhanced vulnerability have linked calbindin to nigrostriatal dopamine neuron survival [116][117][118] while neuromelanin has been negatively associated [119][120][121][122]. However, a definitive connection of either of these markers with nigrostriatal damage remains to be established.…”

Nigrostriatal Damage Preferentially Decreases a Subpopulation of α6β2* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum

“…Identification of the molecular markers linked to this differential depletion may provide insight about the mechanisms responsible for the nigrostriatal neurodegeneration. Indeed, it has been suggested that calbindin is positively linked to nigrostriatal dopamine neuron survival (Gerfen et al, 1987a;German et al, 1992;Liang et al, 1996), whereas neuromelanin has been negatively associated (Hirsch et al, 1988;Herrero et al, 1993;Zecca et al, 2003;McCormack et al, 2004), although a definitive relationship of either of these markers with nigrostriatal damage is lacking. In the present study, a clear correlation is observed between the loss of the very-high-affinity E11A-sensitive 125 I-␣-CtxMII binding sites and nigrostriatal damage.…”

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

“…Stereological estimates of normal aging related cell death in humans argue that SNc DA neurons at a higher risk than other neurons in the absence of environmental toxins or pathogens, as they are lost at a significantly higher rate than many other types of neurons (some of which show no appreciable loss over a 6-7-decade span) (109). In mammals with significantly shorter lifespans, loss of SNc DA neurons with age has not been seen reliably, but there is a clear decline in phenotypic markers with age that matches that seen in PD, as well as an increased susceptibility to toxins (4,23,54,60,61,76). Taken together, these studies make a case that SNc DA neurons age more rapidly than the vast majority of the neurons in the brain.…”

“…Stereological estimates of normal aging-related cell death in humans argue that SNc DA neurons at a higher risk than many other types of neuron (109). In mammals with significantly shorter lifespans, loss of SNc DA neurons with age has not been seen reliably, but there is a clear decline in phenotypic markers with age that matches that seen in PD, as well as an increased susceptibility to toxins (4,23,54,61,76). There is also an aging-related decline in SNc mitochondrial function (5), some of which could easily be attributed to the accumulation of mitochondrial DNA mutations with normal aging (10).…”