Genome instability in Alzheimer disease. (January 2017) - Hou, Yujun
Highlights: DNA damage and defects in DNA repair processing may exacerbate AD progression. DNA repair likely plays a role in ameliorating AD pathogenesis directly and indirectly. Polymorphic variants of DNA repair genes may be associated with AD risk. Neuronal vulnerability to a particular type of DNA damage, along with a subsequent decrease in repair, may cause these adducts to accumulate with age and promote brain aging and neurodegeneration. Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component.