Aging and MPTP-Sensitivity Depend on Molecular and Ultrastructural Signatures of Astroglia and Microglia in Mice Substantia Nigra

Abstract BackgroundBoth astroglia and microglia show region-specific distribution pattern in the central nervous system and often maladapt to age-associated alterations within their niche. Studies on autopsied substantia nigra of Parkinson’s disease (PD) patients and experimental models propose gliosis as a trigger for neuronal loss. Epidemiological studies propose an ethnic bias in PD prevalence, since Caucasians are more susceptible than non-whites living in Asia and Africa. Similarly, different mice strains are variably sensitive to the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We had earlier likened divergent MPTP-sensitivity of C57BL/6J and CD-1 mice with differential susceptibility to PD, based on differences in neuronal numbers.MethodsHere we examined whether the variable susceptibility was also incumbent to inter-strain differences in the glial features in the substantia nigra pars compacta (SNpc) of C57BL/6J and CD-1 mice. We performed unbiased stereology to quantify iba-1 immunoreactive microglia and s100β immunopositive astroglia on immunohistochemically stained sections. Further, ELISA based estimation of pro- inflammatory and anti-inflammatory cytokines was supplemented with estimation of enzymes like fractalkine, hemeoxygenase, and monoamine oxidases A and B. Electron microscopy was performed to compare the effects on the organelles.ResultsStereological counts showed more microglia and fewer astrocytes in the substantia nigra of MPTP-susceptible normal C57BL/6J mice, which suggests persistence of an immune-vigilant state. MPTP caused induction of microgliosis and astrogliosis in both strains, suggesting the involvement of these cells in pathogenesis. ELISA of pro-inflammatory cytokines in the ventral-midbrain revealed augmentation of TNF-α and IL-6 at middle-age in both strains that reduced at old-age, suggesting middle-age as a critical, inflamm-aging associated time-point. TNF-α levels were persistently high in C57BL/6J, through aging and post-MPTP; while IL-6 and IL-1β were upregulated at old-age. CD-1 had higher levels of anti-inflammatory cytokine TGF-β. MPTP-challenge caused upregulation of enzymes MAO-A, MAO-B and iNOS in both strains. Post-MPTP enhancement in fractalkine and hemeoxygenase-1, may be neuronal compensatory signals. Lastly, ultrastructural observations of elongated mitochondria in astroglia and microglia vis-à-vis the shrunken ones in neurons, suggest upscaling of their functions with neurotoxic consequences.ConclusionsThus, astroglia and microglia play a critical role in modulating aging and the susceptibility of an individual to PD.