Objective: To examine whether the variable sensitivity of dopaminergic neurons of the substantia nigra pars compacta -SNpc- in C57BL/6J and CD-1 mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/ MPTP is governed by glia through their specific molecular properties.
Background: Both astroglia and microglia show region-specific distribution in CNS and often show reactive phenotypes to age-associated alterations. Studies on autopsied SN of Parkinson disease (PD) patients and experimental models propose gliosis as a point-of-initiation for neuronal deficits. Besides, epidemiological studies propose an ethnic bias in PD prevalence, since Caucasians are more susceptible than non-whites. Since different mice strains are variably sensitive to MPTP, we had earlier equated variable MPTP-sensitivity of C57BL/6J and CD-1 mice with variable susceptibility to PD, based on the numbers of SN neurons.
Method: Astroglia and microglia were identified by S100b and IBA-1 labeling respectively and quantified by stereology. A panel of pro- and anti-inflammatory cytokines was assessed by ELISA and few other proteins by immunoblotting. Ultrastructural changes were examined by transmission electron microscopy.
Results: Stereological quantification showed relatively larger number of microglia and fewer astrocytes in the SN of normal C57BL/6J mice, suggesting persistence of an immune-vigilant state. MPTP caused microgliosis and astrogliosis in both strains, hinting at their involvement in pathogenesis. ELISA of pro-inflammatory cytokines in 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/6J, through aging and post-MPTP; while IL-6 and IL-1β were increased at old-age. CD-1 had high levels of anti-inflammatory cytokine TGF-β. MPTP upregulated enzymes MAO-A, MAO-B and iNOS in both strains. MPTP-induced increase 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.
Conclusion: Both, astroglia and microglia may moderate aging and vulnerability to Parkinson disease.
To cite this abstract in AMA style:
P. Alladi, A. Abhilash, U. Bharti, R. Santhosh Kumar, M. Philip, B. Chandrasekhar Sagar. Differences in Molecular and Ultrastructural profiles of astroglia and microglia in substantia nigra of two different mice strains in normal aging and experimental Parkinsonism [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/differences-in-molecular-and-ultrastructural-profiles-of-astroglia-and-microglia-in-substantia-nigra-of-two-different-mice-strains-in-normal-aging-and-experimental-parkinsonism/. Accessed October 12, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/differences-in-molecular-and-ultrastructural-profiles-of-astroglia-and-microglia-in-substantia-nigra-of-two-different-mice-strains-in-normal-aging-and-experimental-parkinsonism/