Exposure to lead (Pb) and the developmental origin of oxidative DNA damage in the aging brain

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Abstract
SPECIFIC AIMSThe clinical manifestations of Alzheimer’s disease (AD) appear in old age; however, the initial events that trigger this disease may begin very early in life. Similar to cancer, a progressive accumulation of damage occurs in AD patients during a long asymptomatic period (perhaps decades) before the disease is clinically detectable. The progressive and latent nature of neurodegeneration suggests that the triggering event occurs much earlier in life. Our recent work on rodents showed that neonatal exposure to lead (Pb) results in an over expression of the β amyloid (Aβ) precursor protein (APP) gene and a commensurate elevation in the levels of APP and its proteolytic product, the Aβ peptide, in old age. Aβ is cytotoxic and known to generate reactive oxygen species and promote neurodegeneration in the aging brain. To corroborate whether early exposure to Pb impacts the onset of oxidative damage late in life, we measured the levels of 8-hydroxyl-2′-deoxyguanosine (oxo8dG) and the associated activ...
Funding Information
  • National Institutes of Health (ES08104, ES013022, RR16457)
  • National Institutes of Health (AG18379, AG18884)
  • Alzheimer's Association
  • National Science Foundation (NSF-EPSCoR EPS-0091995)