Loss of Adaptive DNA Breaks in Alzheimer’s Disease Brains

Author:

Zhang Xiaoyu12,Haeri Mohammad34,Swerdlow Russell H.356,Wang Ning12

Affiliation:

1. Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA

2. Institute of Reproduction and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS, USA

3. University of Kansas Alzheimer’s Disease Center, Kansas City, KS, USA

4. Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

5. Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA

6. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA

Abstract

Background: DNA breaks accumulate in Alzheimer’s disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks. Objective: To characterize how AD impacts adaptive DNA breaks at nervous system genes. Methods: We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. Results: Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains. Conclusions: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.

Publisher

IOS Press

Subject

Psychiatry and Mental health,Geriatrics and Gerontology,Clinical Psychology,General Medicine,General Neuroscience

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