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DNA Double-Strand Break Accumulation in Alzheimer’s Disease: Evidence from Experimental Models and Postmortem Human Brains

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Abstract

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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Data Availability

The data generated and analyzed in this study are available from the corresponding author on reasonable request.

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Acknowledgments

This work was supported by the William and Ella Owens Medical Research Foundation, Department of Defense grant W81XWH-17-1-0062, and the Division of Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center.

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Authors and Affiliations

  1. Department of Neurology, College of Medicine, University of Tennessee Health Science Center, 855 Monroe Avenue, 415 Link Building, Memphis, TN, 38163, USA

    Nidheesh Thadathil, David F. Delotterie, Jianfeng Xiao, Michael P. McDonald & Mohammad Moshahid Khan

  2. Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA

    Roderick Hori

  3. Department of Anatomy & Neurobiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Michael P. McDonald

  4. Center for Muscle, Metabolism and Neuropathology, Division of Rehabilitation Sciences and Department of Physical Therapy, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN, USA

    Mohammad Moshahid Khan

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Thadathil, N., Delotterie, D.F., Xiao, J. et al. DNA Double-Strand Break Accumulation in Alzheimer’s Disease: Evidence from Experimental Models and Postmortem Human Brains. Mol Neurobiol 58, 118–131 (2021). https://doi.org/10.1007/s12035-020-02109-8

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