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<p>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 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/6&#xa0;J and CD-1 mice with differential susceptibility to PD, based on the numbers of SN neurons. We examined whether the variability was incumbent to inter-strain differences in glial features of male C57BL/6&#xa0;J and CD-1 mice. Stereological counts showed relatively more microglia and fewer astrocytes in the SN of normal C57BL/6&#xa0;J mice, suggesting persistence of an immune-vigilant state. MPTP-induced microgliosis and astrogliosis in both strains suggest their involvement in pathogenesis. ELISA of pro-inflammatory cytokines in the ventral-midbrain revealed augmentation of TNF-<i>α</i> 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-<i>α</i> levels were high in C57BL/6&#xa0;J, through aging and post-MPTP, while IL-6 and IL-1<i>β</i> were upregulated at old age. CD-1 had higher levels of anti-inflammatory cytokine TGF-<i>β</i>. 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-à-vis the shrunken ones in neurons suggest a scale-up of their functions with neurotoxic consequences. Thus, astroglia and microglia may modulate aging and PD susceptibility.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月20日

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  • P. L. Abhilash,
  • Upasna Bharti,
  • Santhosh Kumar Rashmi,
  • Mariamma Philip,
  • T. R. Raju,
  • Bindu M. Kutty,
  • B. K. Chandrasekhar Sagar,
  • Phalguni Anand Alladi

摘要

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 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/6 J and CD-1 mice with differential susceptibility to PD, based on the numbers of SN neurons. We examined whether the variability was incumbent to inter-strain differences in glial features of male C57BL/6 J and CD-1 mice. Stereological counts showed relatively more microglia and fewer astrocytes in the SN of normal C57BL/6 J mice, suggesting persistence of an immune-vigilant state. MPTP-induced microgliosis and astrogliosis in both strains suggest 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 high in C57BL/6 J, 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 neuron-associated compensatory signals. Ultrastructural observations of elongated astroglial/microglial mitochondria vis-à-vis the shrunken ones in neurons suggest a scale-up of their functions with neurotoxic consequences. Thus, astroglia and microglia may modulate aging and PD susceptibility.