The DNA Replication Stress Hypothesis of Alzheimer’s Disease
Open accessAbstract
A well-recognized theory of Alzheimer’s disease (AD) pathogenesis suggests ectopic cell cycle events to mediate neurodegeneration. Vulnerable neurons of the AD brain exhibit biomarkers of cell cycle progression and DNA replication suggesting a reentry into the cell cycle. Chromosome reduplication without proper cell cycle completion and mitotic division probably causes neuronal cell dysfunction and death. However, this theory seems to require some inputs in accordance with the generally recognized amyloid cascade theory as well as to explain causes and consequences of genomic instability (aneuploidy) in the AD brain. We propose that unscheduled and incomplete DNA replication (replication stress) destabilizes (epi)genomic landscape in the brain and leads to DNA replication “catastrophe” causing cell death during the S phase (replicative cell death). DNA replication stress can be a key element of the pathogenetic cascade explaining the interplay between ectopic cell cycle events and genetic instabilities in the AD brain. Abnormal cell cycle reentry and somatic genome variations can be used for updating the cell cycle theory introducing replication stress as a missing link between cell genetics and neurobiology of AD.
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DNA replication stress and insufficient repair mechanisms may contribute to the development of somatic mutations in neurons.
“DNA replication stress and insufficient repair mechanisms may contribute to the development of somatic mutations in neurons [246]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [246]
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The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?
Fielder, E., von Zglinicki, T., & Jurk, D. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-161221 · Cited by 126 · see citing works
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
“As these cells do not typically divide, DNA replication stress and insufficient repair mechanisms may contribute to the development of somatic mutations in neurons (Yurov et al., 2011), rendering these cells uniquely susceptible to eventual death as is observed during the neurodegenerative phase of AD.”
BackgroundGenome instability in Alzheimer disease
Hou, Y., Song, H., Croteau, D. L., Akbari, M., & Bohr, V. A. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.04.005 · Cited by 120 · see citing works
- Authors
- Yurov, Y. B., Vorsanova, S. G., & Iourov, I. Y.
- Affiliations
- Mental Health Research Center of Russian Academy of Medical Sciences (RU)
- Corresponding author
- Iourov, Ivan Y.
- Venue
- The Scientific World JOURNAL
- Publisher
- Wiley
- Published
- 2011
- Volume
- 11
- Pages
- 2602-2612
- ISSN
- 1537-744X (ISSN-L)
- PMC
- PMC3254013
- OpenAlex
- W2105567273
- Cited by
- 110
- References
- 0
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 12 · 2021: 12 · 2020: 9 · 2019: 10 · 2018: 5 · 2017: 8 · 2016: 8 · 2015: 8 · 2014: 8 · 2013: 9 · 2012: 7
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- The Scientific World JOURNAL (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Federal Ministry of Education and Research (RUS 09/006, RUS 11/002)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- Alzheimer's disease, replication stress, neuronal cell death, genomic instability, aneuploidy, amyloid hypothesis, S phase, epigenetic instability, neurodegeneration
- MeSH terms
- Alzheimer Disease, Cell Cycle, DNA Replication, Humans, Models, Biological, Stress, Physiological, S Phase
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