Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: Diminished compensatory mechanisms as a prelude to parkinsonism

Abstract

Aging is the most prominent risk factor for Parkinson's disease. Yet, consensus of how advancing age may predispose the dopamine (DA) system to parkinsonism is lacking. Three age ranges of female rhesus monkeys, 8-9, 15-17, and 21-31 years, received unilateral DA depletion with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Morphological and biochemical analyses of DA-depleted and intact hemispheres revealed three primary findings: (1) The intact striatum exhibited age-related declines in dopamine (DA) and homovanillic acid (HVA) that were present by middle age; (2) In the MPTP-treated striatum, the compensatory increase in DA activity was absent in old monkeys; and (3) Age-associated morphological changes included declines in the density of tyrosine hydroxylase (TH) positive fibers in striatum, decreased nigral soma size, and optical density of TH, but no significant loss of neurons. These findings suggest that aging produces changes in the nigrostriatal DA system that approach the threshold for expression of parkinsonian features, and that progressive impairment of plasticity may be central to the role of aging in development of parkinsonism.

Mitochondrial ATP-sensitive potassium channels enhance angiotensin-induced oxidative damage and dopaminergic neuron degeneration. Relevance for aging-associated susceptibility to Parkinson’s disease

“…Recent evidence suggests that dopaminergic and renin-angiotensin systems directly counterregulate each other in renal cells (Gildea 2009) and also in the nigrostriatal system (Villar-Cheda et al 2010a), and that abnormal counterregulation between dopamine and angiotensin II plays an important role in degenerative changes Li et al 2008;Rodriguez-Pallares et al 2008). Interestingly, several studies have shown that there is an agingrelated decrease in dopamine release, which results in a progressive decrease in motor activity (Collier et al 2007;Gerhardt et al 2002), and may be responsible for the above mentioned aging-related increase in angiotensin activity (Villar-Cheda et al 2010a,b).…”

“…Advancing age itself is one of the most significant risk factors for the development of neurodegenerative diseases such as Parkinson's disease (PD; Collier et al 2007;Cruz-Muros et al 2009;Deng et al 2006;McCormac et al 2004). Brain possesses a local reninangiotensin system (Mckinley et al 2003;Saavedra 2005), and we have recently observed an agingrelated increase in angiotensin activity in the nigra that leads to pro-inflammatory and pro-oxidative changes, which may constitute a major factor in the increased risk of PD with aging (Villar-Cheda et al 2010b).…”

Aging and Sedentarism Decrease Vascularization and VEGF Levels in the Rat Substantia Nigra. Implications for Parkinson's Disease

“…Perfusion deficits have also been observed before the onset of clinical symptoms in other neurodegenerative disorders, which suggests that the deficits contribute to the pathogenesis of the disease (Storkebaum and Carmeliet, 2004). Conflicting results have been obtained in different studies, with either an age-dependent depletion or no change in DA neuron counts, which may be attributable to a number of methodological variables (Kubis et al, 2000;Collier et al, 2007). However, the present results support observations of a progressive functional decline in the SNc and increased vulnerability to injury with age.…”

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).…”