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

Abstract

Both astroglia and microglia show region-specific distribution in CNS and often maladapt to age-associated alterations within their niche. Studies on autopsied substantia nigra (SN) of Parkinsons 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 the numbers of SN neurons. Here, we examined whether the variability was incumbent to inter-strain differences in glial features of male C57BL/6J and CD-1 mice. Stereological counts showed relatively more microglia and fewer astrocytes in the SN of 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- 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- levels were high in C57BL/6J, through aging and post-MPTP; while IL-6 and IL-1{beta} were upregulated at old-age. CD-1 had higher levels of anti-inflammatory cytokine TGF-{beta}. 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 neuron-associated compensatory signals. Ultrastructural observations of elongated astroglial/microglial mitochondria vis-a-vis the shrunken ones in neurons, suggest a scale-up of their functions with neurotoxic consequences. Thus, astroglia and microglia modulate aging and PD-susceptibility. HighlightsO_LISubstantia nigra of C57BL/6J and CD-1 show no baseline differences in glial numbers C_LIO_LIBoth mice show age and MPTP-induced gliosis in the substantia nigra pars compacta C_LIO_LICD-1 nigra has lower levels of pro- and higher levels of anti-inflammatory cytokines C_LIO_LITilt of balance between pro- and anti-inflammatory cytokines begins at middle age C_LIO_LIAstrocytes and microglia show elongated mitochondria and intact ER upon MPTP-injection C_LI