DNA Damage and Senescence in the Aging and Alzheimer’s Disease Cortex Are Not Uniformly Distributed
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Abstract
Alzheimer’s disease (AD) is a neurodegenerative illness with a typical age of onset exceeding 65 years of age. The age dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. The connection between aging and the loss of genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells has been reported to increase with age, and their senescence-associated secreted products are likely contributing factors to age-related illnesses. We tracked DNA damage with 53BP1 and cellular senescence with p16 immunostaining of human post-mortem brain samples. We found that DNA damage was significantly increased in the BA9 region of the AD cortex compared with the same region in unaffected controls (UCs). In the AD but not UC cases, the density of cells with DNA damage increased with distance from the pia mater up to approximately layer V and then decreased in deeper areas. This pattern of DNA damage was overlaid with the pattern of cellular senescence, which also increased with cortical depth. On a cell-by-cell basis, we found that the intensities of the two markers were tightly linked in the AD but not the UC brain. To test whether DNA damage was a causal factor in the emergence of the senescence program, we used etoposide treatment to damage the DNA of cultured mouse primary neurons. While DNA damage increased after treatment, after 24 h, no change in the expression of senescence-associated markers was observed. Our work suggests that DNA damage and cellular senescence are both increased in the AD brain and increasingly coupled. We propose that in vivo, the relationship between the two age-related processes is more complex than previously thought.
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Flagged first, then by citations
- Authors
- Gutta, G., Mehta, J., Kingston, R., Xie, J., Brenner, E., Ma, F., & Herrup, K.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Ma, Fulin
- Venue
- Biomedicines
- Publisher
- MDPI AG
- Published
- 2024-06-14
- Volume
- 12
- Issue
- 6
- Pages
- 1327
- ISSN
- 2227-9059 (ISSN-L)
- PMC
- PMC11201767
- OpenAlex
- W4399670596
- Cited by
- 6
- References
- 17
- Citations by year
- 2026: 2 · 2025: 4
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Biomedicines (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- PA Department of State (4100087331, 1RF1NS120922)
- National Institutes of Health (4100087331, 1RF1NS120922)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- Alzheimer's disease, DNA damage, cellular senescence, brain aging, frontal cortex, 53BP1, p16, cortical depth, postmortem brain, etoposide, senescence-associated secretory phenotype, neuronal senescence
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