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Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

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Abstract

Phosphorylation of the histone family is not only a response to cell signaling stimuli, but also an important indicator of DNA damage preceding apoptotic changes. While astrocytic degeneration, including DNA damage, has been reported in Alzheimer disease (AD), its pathogenetic significance is somewhat unclear. In an effort to clarify this, we investigated the expression of γH2AX as evidence of DNA damage in astrocytes to elucidate the role of these cells in the pathogenesis of AD. In response to the formation of double-stranded breaks in chromosomal DNA, serine 139 on H2AX, a 14-kDa protein that is a member of the H2A histone family and part of the nucleosome structure, becomes rapidly phosphorylated to generate γH2AX. Using immunocytochemical techniques, we found significantly increased levels of γH2AX in astrocytes in regions know to be vulnerable in AD, i.e., the hippocampal regions and cerebral cortex. These results suggest that astrocytes contain DNA damage, possibly resulting in functional disability, which in turn reduces their support for neurons. These findings further define the role of astrocyte dysfunction in the progression of AD.

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Acknowledgments

Work in the authors’ laboratories is supported by the National Institutes of Health, the Alzheimer’s Association, and by Philip Morris USA Inc. and Philip Morris International.

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Authors and Affiliations

  1. Department of Pathology, Case Western Reserve, 2103 Cornell Road, Cleveland, OH, 44106, USA

    Na-Hye Myung, Xiongwei Zhu, Robert B. Petersen, Sandra L. Siedlak, George Perry, Mark A. Smith & Hyoung-gon Lee

  2. Department of Pathology, Dankook University College of Medicine, Chonan, Korea

    Na-Hye Myung

  3. Christopher Center, Sun Health Research Institute, Sun City, AZ, USA

    Inna I. Kruman

  4. Department of Pathology, University of Maryland, Baltimore, MD, USA

    Rudy J. Castellani

  5. College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA

    George Perry

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  1. Na-Hye Myung
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  2. Xiongwei Zhu
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  3. Inna I. Kruman
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  4. Rudy J. Castellani
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  6. Sandra L. Siedlak
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  7. George Perry
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  8. Mark A. Smith
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  9. Hyoung-gon Lee
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Correspondence to Hyoung-gon Lee.

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Myung, NH., Zhu, X., Kruman, I.I. et al. Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes. AGE 30, 209–215 (2008). https://doi.org/10.1007/s11357-008-9050-7

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  • DOI: https://doi.org/10.1007/s11357-008-9050-7

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