Objective: We aimed to investigate the contribution of glial cells activation and immune cells infiltration in the selective vulnerability of dopaminergic neurons within the midbrain in a non-human primate model of Parkinson’s Disease (PD). Structural and functional alterations of the blood-brain barrier (BBB) within specific regions of the midbrain have been also evaluated.

Background: Nigrosome, a region identified by poor neuropil calbindin-D28K (CB) immunostaining within the substantia nigra pars compacta (SNpc), contains the largest proportion of dopaminergic neurons affected in PD. However, the factors determining why these neurons are selectively vulnerable while others resist the degenerative process in PD are still poorly understood.

Method: Parkinsonism was induced by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a low dose regimen (0.5 mg/kg every 2 weeks) to obtain partial, slow and progressive degeneration of the dopaminergic system in non-human primates. Based on immunostaining for CB, the dopaminergic midbrain region was subdivided in nigrosome (CB-poor zone) and matrix (CB-rich zones). Adjacent serial sections were then immunostained with markers for glial cells (IBA1 and GFAP), T and B lymphocytes (CD4 and CD20) and brain microvasculature (CD31, GLUT1, ZO-1) to evaluate the role of neuroinflammation and vasculature in the selective vulnerability of dopaminergic neurons within the nigrosome.

Results: MPTP monkeys showed a massive glial activation in the whole midbrain, but no major differences were observed comparing nigrosome and matrix regions. Remarkably, nigrosome region is normally much more vascularized in comparison with the rest of dopaminergic midbrain. This probably makes this region more susceptible to immune cells infiltration under pathological conditions as observed in the nigrosome but not in the matrix of parkinsonian monkeys.

Conclusion: These data suggest that the higher vascular density within the nigrosome may represent the main route of entry of immune cells in the dopaminergic midbrain. The increased infiltration of T and B cells in the nigrosome (but not in the matrix) could contribute to the selective vulnerability of dopaminergic neurons in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neurovascular-and-immune-determinants-of-selective-vulnerability-of-dopaminergic-neurons-in-parkinsons-disease/