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, 30 (4), 209-15

Evidence of DNA Damage in Alzheimer Disease: Phosphorylation of Histone H2AX in Astrocytes

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Evidence of DNA Damage in Alzheimer Disease: Phosphorylation of Histone H2AX in Astrocytes

Na-Hye Myung et al. Age (Dordr).

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 gamma H2AX 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 gamma H2AX. Using immunocytochemical techniques, we found significantly increased levels of gamma H2AX 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.

Figures

Fig. 1a–d
Fig. 1a–d
Expression of γH2AX in astrocytes in Alzheimer disease (AD). Virtually no nuclear H2AX is detected in the CA4 region of the hippocampus in control cases (a), even though a large number of astrocytes are present, as seen in an adjacent serial section immunostained with anti-GFAP (b). However, specific nuclear immunoreactivity is seen in many astroglial cells in the hippocampus of a 91-year-old AD case (c), while the number of GFAP-positive astrocytes in an adjacent serial section (d) is similar to that in the control case. Individual cells are visualized by counterstaining with hematoxylin. The pyramidal neurons remain unlabeled for H2AX (arrows in a and c). Asterisks Landmark vessels. Bar  100 μm
Fig. 2a–d
Fig. 2a–d
In an 82-year-old AD case, double-labeling immunocytochemistry confirms the localization of H2AX in astrocytes. a, b H2AX-positive nuclei (blue, arrows) display complete overlap with astrocytes detected with antisera to GFAP (brown). Only a small percentage of astrocytes do not display H2AX (b, arrowhead). c (and inset) Microglia are stained brown and never contain H2AX positive nuclei (blue). d Neurofibrillary tangles, stained brown, also do not contain H2AX (blue). Barsa, c, d 50 μm; b 10 μm

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