Ageing and MPTP-sensitivity depend on molecular and ultrastructural signatures of astroglia and microglia in mice substantia nigra

Abstract

ABSTRACTBoth astroglia and microglia show region-specific distribution in CNS 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. 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 of male C57BL/6J and CD-1 mice. Stereological counts showed more microglia and fewer astrocytes in the substantia nigra of MPTP-susceptible normal C57BL/6J mice, suggesting persistence of an immune-vigilant state. MPTP-induced microgliosis and astrogliosis in both strains, suggests their involvement 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 ageing 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 astroglial/microglial mitochondria vis-à-vis the shrunken ones in neurons, suggest upscaling of their functions with neurotoxic consequences. Thus, astroglia and microglia modulate ageing and PD-susceptibility.Significance statementPeople of Caucasians ancestry are more susceptible to Parkinson’s disease, than the Asians, for reasons not completely understood. 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 secrete low levels of neuroinflammatory proteins and their gut microbiota is typical. The astrocytic and microglia mitochondria may hold the key to cure neurodegeneration.