Project Summary: Accumulating genomic damage to neurons is a cardinal feature of Alzheimer’s disease and the normal aging process. Although cognitive stimulation has been shown to attenuate the debilitating effects of Alzheimer’s disease on brain function, stimulus-dependent neuronal activity also poses an inherent risk to genomic stability across the long lifespan of central nervous system (CNS) neurons insofar as activity-driven transcriptional responses proceed via the transient induction of local DNA double-stranded breaks (DSBs), which must be repeatedly repaired. DSB accumulation is an early feature of Alzheimer’s disease. Yet, the extent to which these Alzheimer’s disease-associated breaks represent unrepaired sites of activity-induced DSBs, and whether postmitotic neurons employ distinctive repair mechanisms to maintain genomic integrity in the face of these challenges, remain unclear. In the course of investigating features of the neuronal activity-dependent transcriptional program, we uncovered a biochemical coupling of neuronal activity to DNA repair mechanisms. We find that a novel form of the NuA4 chromatin remodeling/DNA repair complex assembles around the neuronal-specific activity-regulated transcription factor NPAS4 at activity-responsive gene regulatory elements in the mouse brain, with NPAS4:NuA4 disruption leading to local defects in DNA repair, increased genomic instability, and shortened lifespan. To gain further insight into the nature of these recurrent neuronal activity- induced DNA break/repair mechanisms and their contribution to Alzheimer’s disease- and aging-associated cognitive decline, we propose: 1) to map the landscape of activity-induced DSBs in wild-type mice and mouse models of Alzheimer’s disease, 2) to assess the contribution of stimulus-induced neuronal DSBs to age- associated genomic alterations, and 3) to characterize the specialized DSB repair mechanisms active in human postmitotic neurons with the hope of finding inhibitors or activators of the repair process that might ultimately serve as starting points for the development of therapeutics for treating Alzheimer’s disease. The proposed studies will thus provide new insights into the distinctive DNA repair systems active in CNS neurons, clarify the contribution of recurrent neuronal activity-induced DNA breaks to Alzheimer’s disease- and age-associated genomic instability, and ultimately provide new opportunities for the development of therapeutic strategies to combat Alzheimer’s disease.