Evidence linking genetics, environment, and epigenetics to impaired DNA repair in Alzheimer's disease.
Increasing evidence suggests that the repair of DNA lesions, particularly oxidative DNA lesions, might be compromised in Alzheimer's disease (AD). Studies performed in brains and peripheral tissues of both AD patients and individuals affected by mild cognitive impairment (MCI) revealed that oxidative DNA damage is one of the earliest detectable events during the progression from healthy aging to dementia. Moreover, the increase in DNA damage is paralleled by a decrease in DNA repair activities. Several hypotheses are currently tested in order to explain the decreased DNA repair activity observed in MCI and AD subjects. Some authors have suggested that mutations or polymorphisms in DNA repair genes might impair DNA repair. However, this hypothesis does not seem to be confirmed by recent genetic association studies. Others suggest that DNA repair proteins might be inactivated by oxidative induced post-translational modifications or degradation. There is also indication that different isoforms of the same repair protein might be involved in the progression from early to late stages AD. Moreover, a widespread activation of DNA repair pathways might generate death signals ending with neuronal apoptosis. A link between environmental induced epigenetic modification, oxidation, and repair of AD related genes has been also proposed. Most of these studies have been performed during the last few years, and we are still at the beginning of understanding the complex interplay between oxidative DNA damage, DNA repair, and neuronal death in the brain leading to Alzheimer's dementia, making this topic an exciting and promising field for future investigation.
Coppedè
Fabio
F
Department of Neuroscience, University of Pisa, Pisa, Italy. f.coppede@geog.unipi.it
Migliore
Lucia
L
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics* / Q000502:physiology*; D004777:Environment; D044127:Epigenesis, Genetic; D006801:Humans; D009154:Mutation / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D011110:Polymorphism, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology