Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease.

ABSTRACT: The maintenance of genomic integrity is essential for normal cellular functions. However, it is difficult to maintain over a lifetime in postmitotic cells such as neurons, in which DNA damage increases with age and is exacerbated by multiple neurological disorders, including Alzheimer's disease (AD). Here we used immunohistochemical staining to detect DNA double strand breaks (DSBs), the most severe form of DNA damage, in postmortem brain tissues from patients with mild cognitive impairment (MCI) or AD and from cognitively unimpaired controls. Immunostaining for ?H2AX-a post-translational histone modification that is widely used as a marker of DSBs-revealed increased proportions of ?H2AX-labeled neurons and astrocytes in the hippocampus and frontal cortex of MCI and AD patients, as compared to age-matched controls. In contrast to the focal pattern associated with DSBs, some neurons and glia in humans and mice showed diffuse pan-nuclear patterns of ?H2AX immunoreactivity. In mouse brains and primary neuronal cultures, such pan-nuclear ?H2AX labeling could be elicited by increasing neuronal activity. To assess whether pan-nuclear ?H2AX represents DSBs, we used a recently developed technology, DNA damage in situ ligation followed by proximity ligation assay, to detect close associations between ?H2AX sites and free DSB ends. This assay revealed no evidence of DSBs in neurons or astrocytes with prominent pan-nuclear ?H2AX labeling. These findings suggest that focal, but not pan-nuclear, increases in ?H2AX immunoreactivity are associated with DSBs in brain tissue and that these distinct patterns of ?H2AX formation may have different causes and consequences. We conclude that AD is associated with an accumulation of DSBs in vulnerable neuronal and glial cell populations from early stages onward. Because of the severe adverse effects this type of DNA damage can have on gene expression, chromatin stability and cellular functions, DSBs could be an important causal driver of neurodegeneration and cognitive decline in this disease.

SUBMITTER: Shanbhag NM 

PROVIDER: S-EPMC6524256 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature