ABSTRACTGlia show region-specific distribution in CNS and often mal-adapt to age-associated alterations in their niche. Some studies on autopsied nigra of Parkinson’s disease (PD) patients and experimental models propose gliosis as a putative trigger of neuronal loss. Epidemiological studies propose an ethnic bias in PD prevalence, as Caucasians are more susceptible than non-whites. Similarly, different mice strains are variably sensitive to MPTP. 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.Here we examined whether the variability was also incumbent to inter-strain differences in glial features. Stereological counts showed more microglia and fewer astrocytes in the nigra of MPTP-susceptible normal C57BL/6J mice, suggesting persistence of an immune-vigilant state. Pronounced MPTP-induced microgliosis and astrogliosis in both strains suggest glial involvement in pathogenesis. ELISA-based estimation of pro-inflammatory cytokines in the ventral midbrain revealed middle-age specific augmentation of TNF-α and IL-6 that reduced at old-age, suggesting middle-age as a critical, inflamm-aging associated time-point. IL-1β levels declined gradually. Inter-strain differences in TNF-α, including that seen post-MPTP, persisted across ageing while IL-6 and IL-1β showed upregulation at old-age. Levels of anti-inflammatory cytokine TGF-β were higher in CD-1. The enzymes MAO-A, MAO-B and iNOS were upregulated in both strains upon MPTP-challenge. Enhancement in fracktalkine and hemeoxygenase-1, post-MPTP, may be neuronal compensatory signals. Most importantly, ultrastructural observations of elongated glial mitochondria vis-à-vis the shrunken ones in neurons, suggest upscaling of glial functions with neurotoxic consequences. Thus, glia could be key modulators of ageing and disease-susceptibility.Significance statementPeople of Caucasians ancestry are more susceptible to Parkinson’s disease, than the Asians, for reasons not completely understood. Surprisingly, their admixed population “the Anglo-Indians” that lives in India; are much less prone. We designed a disease model around two different laboratory mice i.e. C57BL/6 and CD-1 mice and extrapolated the results to the ethnicities, using a neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). Our study provides objective evidence that astroglia are inherently more and microglia fewer in the mice that resist MPTP. They secret low levels of neuroinflammatory proteins and their gut microbiota is typical. The glial mitochondria may hold the key to cure neurodegeneration.Data availability statementThe data that support the findings of this study are available from the corresponding author upon request.
Assessment of psychophysical capacities for professional work in late middle age and at the beginning of old age