DNA Double-Strand Break Accumulation in Alzheimer’s Disease: Evidence from Experimental Models and Postmortem Human Brains
Open accessAbstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for a majority of dementia cases. AD is characterized by progressive neuronal death associated with neuropathological lesions consisting of neurofibrillary tangles and senile plaques. While the pathogenesis of AD has been widely investigated, significant gaps in our knowledge remain about the cellular and molecular mechanisms promoting AD. Recent studies have highlighted the role of DNA damage, particularly DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of neurodegenerative diseases. In the present study, we tested the hypothesis that accumulation of DNA DSB plays an important role in AD pathogenesis. To test our hypothesis, we examined DNA DSB expression and DNA repair function in the hippocampus of human AD and non-AD brains by immunohistochemistry, ELISA, and RT-qPCR. We observed increased DNA DSB accumulation and reduced DNA repair function in the hippocampus of AD brains compared to the non-AD control brains. Next, we found significantly increased levels of DNA DSB and altered levels of DNA repair proteins in the hippocampus of 5xFAD mice compared to non-transgenic mice. Interestingly, increased accumulation of DNA DSBs and altered DNA repair proteins were also observed in cellular models of AD. These findings provided compelling evidence that AD is associated with accumulation of DNA DSB and/or alteration in DSB repair proteins which may influence an important early part of the pathway toward neural damage and memory loss in AD.
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DNA damage and DDR markers are observed in Alzheimer's disease models and in neurons from postmortem patient brains.
“DNA damage and DDR markers have been observed in models of Alzheimer’s disease154,155 and in neurons in postmortem brains from patients with the disease156.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [155]
The indexed passages are labeled as a Parkinson’s disease paper, despite the supplied Alzheimer’s disease title. Its Results section reports DNA-damage markers in postmortem PD neurons, while its Discussion only briefly mentions a previous study of 53BP1 in AD brain tissue. Searches for AD models and postmortem AD neurons did not retrieve a passage establishing the attributed claim in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredAltered amyloid-β processing and DNA damage have been associated with APOE4 and Alzheimer's disease.
“Altered amyloid-β processing and DNA damage have been associated with APOE4 and AD19–21.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [20]
The supplied passages and the retrieved passages are labeled as a Parkinson’s disease paper, not the cited Alzheimer’s disease paper. Searches for APOE4 and altered amyloid-β processing did not yield passages from our copy of the cited paper, so the attributed association cannot be assessed. (LLM, conf=0.72)
Experimental — accuracy not yet measuredStudies using post-mortem human brain samples show that neurons, astrocytes, and oligodendrocytes accumulate DNA double-strand breaks (DSBs) early in the progression of AD.
“Studies using post-mortem human brain samples show that neurons, astrocytes, and oligodendrocytes accumulate DNA double-strand breaks (DSBs) early in the progression of AD”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [5]
Neurons start accumulating DSBs early in the progression of AD.
“Neurons start accumulating DSBs early in the progression of AD”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [5]
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References 80 · Cited by 94
Research works printed but not linked: 1
- Rose EP, Osterberg VR, Gorbunova V, Unni VK, 2024. Alpha-synuclein modulates the repair of genomic DNA double-strand breaks in a DNA-PK(cs)-regulated manner. Neurobiol Dis 201, 106675. 39306014 PMC11556349
- Authors
- Thadathil, N., Delotterie, D. F., Xiao, J., Hori, R., McDonald, M. P., & Khan, M. M.
- Affiliations
- University of Tennessee Health Science Center (US)
- Corresponding author
- Khan, Mohammad Moshahid
- ORCID
- Venue
- Molecular Neurobiology
- Published
- 2020-09-08
- Volume
- 58
- Issue
- 1
- Pages
- 118-131
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- PMC
- PMC13252816
- OpenAlex
- W3084100386
- Cited by
- 94
- References
- 80
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 19 · 2023: 17 · 2022: 19 · 2021: 4 · 2020: 1
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- William and Ella Owens Medical Research Foundation
- U.S. Department of Defense (W81XWH-17-1-0062)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, DNA double-strand breaks, DNA repair, hippocampus, 5xFAD mice, DNA repair proteins, neurodegeneration, postmortem brain, memory loss
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cells, Cultured, Cricetulus, Disease Models, Animal, DNA Repair, Hippocampus, Humans, Mice, Transgenic, Postmortem Changes, CHO Cells, DNA Breaks, Double-Stranded
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