Cytokine expression and microglial activation in progressive supranuclear palsy

https://doi.org/10.1016/j.parkreldis.2011.06.007Get rights and content

Abstract

Although little is known about the etiology of progressive supranuclear palsy (PSP), genetic and epigenetic factors, oxidative injury and inflammation are thought to contribute to its development and/or progression. Evidence for activated glia involvement in PSP has raised the possibility that neuroinflammation may contribute to its pathogenesis. To investigate the correlation between neuroinflammation and PSP, a comparative study was conducted on the patterns of cytokine expression in different regions of the brains of PSP, Alzheimer’s disease (AD) patients and normal controls. Our results show different patterns of cytokine expression in each disease, with the expression of IL-1β transcripts being significantly higher in the substantia nigra of PSP than in AD and controls, while AD brains had significantly higher IL-1β expression in the parietal cortex compared to PSP and controls. In addition, expression of TGFβ was significantly higher in the cortical areas (particularly frontal and parietal lobes) of AD compared to PSP and controls. These results show a disease-specific topographical relationship among the expression of certain cytokines (IL-1β and TGFβ), microglial activation and neurodegenerative changes, suggesting that these cytokines may contribute to the pathologic process. If so, the use of cytokine-inhibitors and/or other anti-inflammatory agents may be able to slow disease progression in PSP.

Highlights

► We studied expression of cytokine mRNAs in brains of PSP vs. Alzheimer’s disease. ► Higher expression of IL-1β in substantia nigra of brains from PSP patients. ► Higher expression of IL-1β in parietal cortex of brains from Alzheimer’s patients. ► Higher expression of TGFβ in cortical areas of Alzheimer’s patients. ► Correlated IL-1β expression, microglial activation and neurodegeneration.

Section snippets

Brain tissue samples

Post-mortem tissue samples were obtained from brains donated to the CurePSP Society Brain Bank, which operates under a specific IRB protocol approved by the Mayo Clinic. The legal next-of-kin or person with power of attorney signed a consent form allowing the use of donated brain tissue for research purposes. One half of each brain was preserved frozen and used for the isolation of RNA, while the other half was formalin-fixed and used for immunohistochemical studies. The relative abundance of

Comparison of the relative abundance of cytokine transcripts

Transcripts for all four cytokines investigated were consistently detected in all brain groups. The relative abundance of cytokine transcripts was IL-6 > IL-1β > TGFβ > TNFα in all brain groups when expressed as the ratio of the cytokine transcripts relative to that of the house-keeping gene control, GAPDH (Fig. 1A–D). Comparison of the results showed that IL-1β expression levels were higher in the ST and SN of PSP brains, when compared to those of AD and normal controls. In contrast, they were

Discussion

Results of this study indicate that expression of IL-1β as well as the microglial burden in brain tissue are increased in the ST and SN of PSP, and FC and PC of AD brains, the areas primarily affected in each disease. Moreover, the expression of TGFβ and two pro-inflammatory cytokines, IL-6 and TNFα, appeared to be increased in cortical regions of AD. These results point to a correlation between the local alterations in the expression of cytokines, particularly IL-1β, and the areas

Acknowledgments

We are indebted to the CurePSP brain bank for making the study samples available. Funded in part by American Heart Association grant 0350352N to R.F.B. Dr. Dickson is supported by NIH grants P50NS072187 and P50AG16475 and Dr. Litvan NIH grant R01 PAS-03-092.

References (30)

  • C. Bogdan et al.

    Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-β and interleukin-10

    J Biol Chem

    (1992)
  • I. Litvan

    Update on progressive supranuclear palsy

    Curr Neurol Neurosci Rep

    (2004)
  • J.J. Hauw et al.

    Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy)

    Neurology

    (1994)
  • K. Ishizawa et al.

    Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration

    J Neuropathol Exp Neurol

    (2001)
  • S.T. Dheen et al.

    Microglial activation and its implications in the brain diseases

    Curr Med Chem

    (2007)

    • Cited by (0)

    1

    Current address: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.

    View full text
    Copyright © 2011 Elsevier Ltd. All rights reserved.