From DNA repair to neurodegeneration: PARP1 mechanisms and inhibitor strategies in Alzheimer's disease.

PARP1 is a key regulator of DNA damage responses. Reports from cell and animal models suggest that when excessively active, PARP1 exacerbates oxidative stress, mitochondrial dysfunction, and neuroinflammation, which are indicative of Alzheimer's disease (AD) pathogenesis. Recently, there have been great advances in the biology of PARP and modulation of PARP for potential repurposing for neuroprotection. This narrative review details the molecular and interrelationship of PARP1 activity and Alzheimer's progression while trying to implement strategies to mitigate PARP1 activity. This includes molecular pathways, gene associations, and increasing interest in nicotinamide therapies and next-generation PARP-inhibitory drugs. It has been shown that uncontrolled regulation of PARP1 activity will lead to cell death via parthanatos. Increased destruction of cellular NAD+ and ATP, loss of mitochondrial energy, and the unbalanced, unregulated NF-κB neuroinflammation will focus on cell death. Preclinical studies have shown that nicotinamide and NAD+ , cell-permeable PARP1-active agents, enhance mitochondrial function and cognitive resilience. Moreover, brain-penetrant inhibitors such as veliparib and AZD9574 offer enhanced selectivity and access to the central nervous system (CNS). The future calls for CNS-optimized, selective inhibitors that combine safety with bioavailability. This review highlights the exciting possibilities of PARP1 modulation not only for symptomatic relief but also as a marked improvement for the future of treating AD.