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Journal of Neuroinflammation

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Open Access 01-12-2018 | Research

Regional microglia are transcriptionally distinct but similarly exacerbate neurodegeneration in a culture model of Parkinson’s disease

Authors: Eric Wildon Kostuk, Jingli Cai, Lorraine Iacovitti

Published in: Journal of Neuroinflammation | Issue 1/2018

Abstract

Background

Parkinson’s disease (PD) is characterized by selective degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SN) while neighboring ventral tegmental area (VTA) DA neurons are relatively spared. Mechanisms underlying the selective protection of the VTA and susceptibility of the SN are still mostly unknown. Here, we demonstrate the importance of balance between astrocytes and microglia in the susceptibility of SN DA neurons to the PD mimetic toxin 1-methyl-4-phenylpyridinium (MPP⁺).

Methods

Previously established methods were used to isolate astrocytes and microglia from the cortex (CTX), SN, and VTA, as well as embryonic midbrain DA neurons from the SN and VTA. The transcriptional profile of isolated microglia was examined for 21 canonical pro- and anti-inflammatory cytokines by qRT-PCR with and without MPP⁺ exposure. Homo- and heterotypic co-cultures of neurons and astrocytes were established, and the effect of altering the ratio of astrocytes and microglia in vitro on the susceptibility of midbrain DA neurons to the PD mimetic toxin MPP⁺ was investigated.

Results

We found that regionally isolated microglia (SN, VTA, CTX) exhibit basal differences in their cytokine profiles and that activation of these microglia with MPP⁺ results in differential cytokine upregulation. The addition of microglia to cultures of SN neurons and astrocytes was not sufficient to cause neurodegeneration; however, when challenged with MPP⁺, all regionally isolated microglia resulted in exacerbation of MPP⁺ toxicity which was alleviated by inhibition of microglial activation. Furthermore, we demonstrated that isolated VTA, but not SN, astrocytes were able to mediate protection of both SN and VTA DA neurons even in the presence of exacerbatory microglia; however, this protection could be reversed by increasing the numbers of microglia present.

Conclusion

These results suggest that the balance of astrocytes and microglia within the midbrain is a key factor underlying the selective vulnerability of SN DA neurons seen in PD pathogenesis and that VTA astrocytes mediate protection of DA neurons which can be countered by greater numbers of deleterious microglia.

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Title: Regional microglia are transcriptionally distinct but similarly exacerbate neurodegeneration in a culture model of Parkinson’s disease
Authors: Eric Wildon Kostuk
Jingli Cai
Lorraine Iacovitti
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-018-1181-x

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Regional microglia are transcriptionally distinct but similarly exacerbate neurodegeneration in a culture model of Parkinson’s disease

Abstract

Background

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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