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

Acta Neuropathologica Communications

Robert A. Rissman¹  Anthony Adame¹  Eliezer Masliah²  William W. Seeley³  Alissa L. Nana³  Mark D. Evans⁴  Wenjie Mao⁴  Lennart Mucke⁵  Niraj M. Shanbhag⁵ 

[1] 0000 0001 2107 4242, grid.266100.3, Department of Neurosciences, University of California at San Diego, 92093, La Jolla, CA, USA;0000 0001 2107 4242, grid.266100.3, Department of Neurosciences, University of California at San Diego, 92093, La Jolla, CA, USA;0000 0000 9372 4913, grid.419475.a, Present address: Division of Neuroscience, National Institute on Aging, 20892, Bethesda, MD, USA;0000 0001 2297 6811, grid.266102.1, Memory and Aging Center, Department of Neurology, University of California San Francisco, 94158, San Francisco, CA, USA;0000 0001 2297 6811, grid.266102.1, Department of Pathology, University of California San Francisco, 94158, San Francisco, CA, USA;0000 0004 0572 7110, grid.249878.8, Gladstone Institute of Neurological Disease, 94158, San Francisco, CA, USA;0000 0004 0572 7110, grid.249878.8, Gladstone Institute of Neurological Disease, 94158, San Francisco, CA, USA;0000 0001 2297 6811, grid.266102.1, Memory and Aging Center, Department of Neurology, University of California San Francisco, 94158, San Francisco, CA, USA;

关键词: Alzheimer’s disease;    Astrocytes;    DNA damage;    53BP1;    γH2AX;    Neurons;   

DOI  :  10.1186/s40478-019-0723-5

来源: publisher

【 摘 要 】

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 γH2AX—a post-translational histone modification that is widely used as a marker of DSBs—revealed increased proportions of γH2AX-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 γH2AX immunoreactivity. In mouse brains and primary neuronal cultures, such pan-nuclear γH2AX labeling could be elicited by increasing neuronal activity. To assess whether pan-nuclear γH2AX represents DSBs, we used a recently developed technology, DNA damage in situ ligation followed by proximity ligation assay, to detect close associations between γH2AX sites and free DSB ends. This assay revealed no evidence of DSBs in neurons or astrocytes with prominent pan-nuclear γH2AX labeling. These findings suggest that focal, but not pan-nuclear, increases in γH2AX immunoreactivity are associated with DSBs in brain tissue and that these distinct patterns of γH2AX 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.

【 授权许可】

CC BY