Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains

Background: DNA breaks are accumulated in Alzheimer's disease (AD) brains as genomic lesion. However, DNA breaks are also required for normal cognitive function by facilitating the expression of genes related to nervous system function, and this process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks (DSBs). Objective: To characterize how AD impacts DNA breaks at genes related to nervous system function. Methods: DNA single- and double-strand breaks activate poly(ADP-ribose) polymerases (PARPs), which catalyze adjacent proteins with poly(ADP-ribose) (PAR). To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from autopsy brain tissue (frontal cortex) from 3 AD and 3 ND males (78 to 91 years of age) were used for CUT&RUN targeting PAR, followed by genomic sequencing. Results: The AD brains contained 19.9 times more PAR peaks than the ND brains in CUT&RUN analysis, suggesting accumulation of DNA breaks. Interestingly, PAR peaks at nervous system genes are lost in AD brains, and the expression of these genes is downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX (a marker for DSBs). In addition, TOP2B expression is significantly downregulated in AD brains. Conclusion: Our study demonstrates that, despite a net increase in DNA breaks in AD brains, adaptive DNA breaks at nervous system genes are lost in AD brains. This could result from downregulated TOP2B expression and contribute to impaired neuronal and cognitive function in AD patients.