Alzheimer's disease and environmental exposure to lead: the epidemiologic evidence and potential role of epigenetics.
ABSTRACT Several lines of evidence indicate that the etiology of late-onset Alzheimer's disease (LOAD) is complex, with significant contributions from both genes and environmental factors. Recent research suggests the importance of epigenetic mechanisms in defining the relationship between environmental exposures and LOAD. In epidemiologic studies of adults, cumulative lifetime lead (Pb) exposure has been associated with accelerated declines in cognition. In addition, research in animal models suggests a causal association between Pb exposure during early life, epigenetics, and LOAD. There are multiple challenges to human epidemiologic research evaluating the relationship between epigenetics, LOAD, and Pb exposure. Epidemiologic studies are not well-suited to accommodate the long latency period between exposures during early life and onset of Alzheimer's disease. There is also a lack of validated circulating epigenetics biomarkers and retrospective biomarkers of Pb exposure. Members of our research group have shown bone Pb is an accurate measurement of historical Pb exposure in adults, offering an avenue for future epidemiologic studies. However, this would not address the risk of LOAD attributable to early-life Pb exposures. Future studies that use a cohort design to measure both Pb exposure and validated epigenetic biomarkers of LOAD will be useful to clarify this important relationship.
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Conference Paper: Regional Differences in Diagnostic Conversion to Dementia[Show abstract] [Hide abstract]
ABSTRACT: The worldwide increase in dementia incidence has important health and environmental implications for both patients and caregivers. The ability to predict who will develop dementia and to identify risk factors of rapid progression would be a major advance in preventative healthcare. Few studies have surveyed the impact of environmental differences in combination with clinical and genetic factors in modifying dementia progression. We examined variation in diagnostic conversion from normal cognition to dementia in a multi-site cohort of study volunteers. Center-to-Center differences, residence in sparsely populated regions, lower education, older age and more severe cognitive impairment at study entry were associated with conversion to dementia within 5 years following the baseline visit. Because of strong individual Center effects, for which the underlying determinants were not identified, studying diagnostic conversion on a Center-by-Center basis may reveal viable genetic and environmental influences.IV 2014, IEEE; 07/2014
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ABSTRACT: Lead (Pb) neurotoxicity has received renewed interest with the growing evidence that Pb contributes to Alzheimer's disease (AD). However, the mechanism is not clear. In our previous study of long-term Pb exposure in vivo, a brain iron (Fe) overload induced by Pb was observedin elderly rats. It is well known that brain Fe overload is the mechanism of AD. Therefore, we have reason to believe that Pb induced Fe overload and caused neurodegenerative disease. However, the mechanism or route of Pb-induced Fe overload is unknown. In the current study, the effect of Pb exposure on Fe homeostasis in PC12 cells was determined at different Pb-exposure concentrations and periods with differing Fe exposure, and the role of ferroportin 1 (FP1), the sole iron efflux protein, in Pb-induced Fe metabolic disorders was further investigated. The results showed a Pb-induced cellular increase in Fe accompanying a decrease in the expression of FP1 in a concentration- and time-dependent manner in Pb-exposed PC12 cells. Furthermore, FP1 overexpression could attenuate Fe accumulation in Pb-exposed PC12 cells. These results indicated that FP1 might be a novel target to prevent cellular Fe accumulation induced by Pb exposure and subsequent neurotoxic consequences.Toxicology in Vitro 07/2014; 28(8). DOI:10.1016/j.tiv.2014.07.005 · 3.21 Impact Factor
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ABSTRACT: Proanthocyanidins (PCs), a class of naturally occurring flavonoids, had been reported to possess a variety of biological activities, including anti-oxidant, anti-tumor and anti-inflammatory. In this study, we examined the protective effect of PCs against lead-induced inflammatory response in the rat brain and explored the potential mechanism of its action. The results showed that PCs administration significantly improved behavioral performance of lead-exposed rats. One of the potential mechanisms was that PCs decreased reactive oxygen species production and increased the total antioxidant capacity in the brains of lead-exposed rats. Furthermore, the results also showed that PCs significantly decreased the levels of tumor necrosis factor-α, interleukin 1β and cyclooxygenase-2 in the brains of lead-exposed rats. Moreover, PCs significantly decreased the levels of beta amyloid and phosphorylated tau in the brains of lead-treated rats, which in turn inhibited endoplasmic reticulum(ER) stress. PCs also decreased the phosphorylation of protein kinase RNA-like ER kinase, eukaryotic translation initiation factor-2, inositol-requiring protein-1, c-Jun N-terminal kinase, p38 and inhibited nuclear factor-κB nuclear translocation in the brains of lead-exposed rats. In conclusion, these results suggested that PCs could improve cognitive impairments by inhibiting brain oxidative stress and inflammatory response.Food and Chemical Toxicology 07/2014; 72. DOI:10.1016/j.fct.2014.07.033 · 2.61 Impact Factor