Genetic suppression of IKK2/NF-κB in astrocytes inhibits neuroinflammation and reduces neuronal loss in the MPTP-Probenecid model of Parkinson's disease

Neurobiology of Disease
Kelly S KirkleyRonald B Tjalkens

Abstract

Neuroinflammatory activation of glia is considered a pathological hallmark of Parkinson's disease (PD) and is seen in both human PD patients and in animal models of PD; however, the relative contributions of these cell types, especially astrocytes, to the progression of disease is not fully understood. The transcription factor, nuclear factor kappa B (NFκB), is an important regulator of inflammatory gene expression in glia and is activated by multiple cellular stress signals through the kinase complex, IKK2. We sought to determine the role of NFκB in modulating inflammatory activation of astrocytes in a model of PD by generating a conditional knockout mouse (hGfapcre/Ikbk2F/F) in which IKK2 is specifically deleted in astrocytes. Measurements of IKK2 revealed a 70% deletion rate of IKK2 within astrocytes, as compared to littermate controls (Ikbk2F/F). Use of this mouse in a subacute, progressive model of PD through exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) revealed significant protection in exposed mice to direct and progressive loss of dopaminergic neurons in the substantia nigra (SN). hGfapcre/Ikbk2F/F mice were also protected against MPTPp-induced loss in motor activity, loss of striatal ...Continue Reading

Citations

Aug 28, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Baixuan HeXicheng Wang
Dec 4, 2019·Frontiers in Aging Neuroscience·Domenico SergiMaria-Grazia Martinoli
Jul 22, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Sean L HammondRonald B Tjalkens
Feb 5, 2021·Frontiers in Cell and Developmental Biology·Collin M BantleEvgeny Shlevkov
Dec 11, 2020·Cells·Ikuko Miyazaki, Masato Asanuma
Mar 7, 2021·International Journal of Molecular Sciences·Elena V MitroshinaMaria V Vedunova

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