DNA Break-Induced Epigenetic Alterations Promote Plaque Formation and Behavioral Deficits in an Alzheimer’s Disease Mouse Model

The dramatic increase in human longevity over recent decades has contributed to a rising prevalence of age-related diseases, including neurodegenerative disorders such as Alzheimer’s disease (AD). While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE (Inducible Changes to the Epigenome) model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift. We hypothesized that DNA damage induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess Aβ pathology and neuroinflammatory markers. Our findings reveal that DNA damage-induced epigenetic changes significantly affect cognitive behavior and alters Aβ plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage– induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.