Recent developments in the role of DNA damage response and understanding its implications for new therapeutic approaches in Alzheimer's disease

The underlying molecular mechanisms associated with sporadic Alzheimer's disease (AD), a progressive neurodegenerative disease, are not yet fully understood. Adult neurons are post-mitotic cells that may need to survive for as long as the lifespan of the organism itself, they are exposed to DNA damaging stimuli and depend on DNA repair mechanisms for their survival. It is reasonable to hypothesize that inadequate repair of damaged DNA could eventually contribute to the neuronal and synaptic loss characteristic of AD. Recent work related to somatic mutations in neurons, DNA damage response (DDR), role of DNA repair in mitochondria, and cell cycle regulation has highlighted the multifactorial nature of AD. Over the past two decades, most of the clinical trials for AD treatment have targeted the formation of amyloid-β (Aβ) oligomers and clearance of Aβ plaques. As far as we are aware, there are currently very few clinical trials in progress for AD treatment directly targeting enhancing DNA repair, rescuing failing mitochondria, or regulating neuronal apoptosis as the primary mechanism of action. This manuscript reviews recent developments regarding how excessive DNA damage and defective DNA repair may potentiate AD. The main purpose of the review is to contribute towards developing effective therapeutic interventions that can improve outcomes for AD patients.