Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes.
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.
Department of Pathology, Case Western Reserve, 2103 Cornell Road, Cleveland, OH 44106, USA.
Na-Hye
NH
Myung
Xiongwei
X
Zhu
Inna I
II
Kruman
Rudy J
RJ
Castellani
Robert B
RB
Petersen
Sandra L
SL
Siedlak
George
G
Perry
Mark A
MA
Smith
Hyoung-gon
HG
Lee