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Lead Link To Alzheimer's Disease?Early Lead Poisoning May Boost Alzheimer's Brain Chemicals Years Later, Lab Tests ShowJan 2, 2008http://www.cbsnews.com/stories/2008/01/02/health/webmd/main3668022.shtml(WebMD) Lead poisoning in infancy may make Alzheimer's disease more likely decades later, a new study shows.Lead poisoning is a well-known danger, especially for young children. Months or years of lead poisoning can stunt children's growth and damage their brain, kidneys, hearing, and mental development.Early lead poisoning may also tinker with genes in a way that sets the stage for Alzheimer's disease as an adult, according to the new study, which is based on monkeys, not people.The study included two groups of baby monkeys that drank formula for the first 400 days of their life. One group of monkeys got ordinary, lead-free formula. The scientists added low levels of lead to the other group's formula.No health problems were seen in the monkeys during the 23-year study.The scientists checked the monkey's brains at the end of the study. The monkeys that drank the lead-laced formula as babies had higher levels of Alzheimer's-related proteins and more DNA damage than the other monkeys.Lead poisoning in infancy may have made the monkeys' genes make more of the Alzheimer's-related proteins years later, according to the researchers, who included the University of Rhode Island's Nasser Zawia, PhD.Their findings appear in The Journal of Neuroscience.By Miranda HittiReviewed by Louise Chang©2008 WebMD, Inc. All rights reserved.Fish Oil Prevents Alzheimer's Plaques

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More Than 3 Million Have Dementia- - - -1: J Mol Neurosci. 2008;34(1):1-7. Epub 2007 Apr 17.LinksThe environment, epigenetics and amyloidogenesis.Wu J, Basha MR, Zawia NH.Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA, nzawia@....Alzheimer's Disease (AD) is a progressive, irreversible neurodegenerative disease. Despite several genetic mutations (Haass et al., J. Biol. Chem. 269:17741-17748, 1994; Ancolio et al., Proc. Natl. Acad. Sci. USA 96:4119-4124, 1999; Munoz and Feldman, CMAJ 162:65-72, 2000; Gatz et al., Neurobiol. Aging 26:439-447, 2005) found in AD patients, more than 90% of AD cases are sporadic (Bertram and Tanzi, Hum. Mol. Genet. 13:R135-R141, 2004). Therefore, it is plausible that environmental exposure may be an etiologic factor in the pathogenesis of AD. The AD brain is characterized by extracellular beta-amyloid (Abeta) deposition and intracellular hyperphosphorylated tau protein. Our lab has demonstrated that developmental exposure of rodents to the heavy metal lead (Pb) increases APP (amyloid precursor protein) and Abeta production later in the aging brain (Basha et al., J. Neurosci. 25:823-829, 2005a). We also found elevations in the oxidative marker 8-oxo-dG in older animals that had been developmentally exposed to Pb (Bolin et al., FASEB J. 20:788-790, 2006) as well as promotion of amyloidogenic histopathology in primates. These findings indicate that early life experiences contribute to amyloidogenesis in old age perhaps through epigenetic pathways. Here we explore the role of epigenetics as the underlying mechanism that mediates this early exposure-latent pathogenesis with a special emphasis on alterations in the methylation profiles of CpG dinucleotides in the promoters of genes and their influence on both gene transcription and oxidative DNA damage. PMID: 181576522: free online:http://www.jneurosci.org/cgi/content/full/25/4/823J Neurosci. 2005 Jan 26;25(4):823-9.The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain.Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH.Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA.The fetal basis of adult disease (FeBAD) hypothesis states that many adult diseases have a fetal origin. According to FeBAD, injury or environmental influences occurring at critical periods of organ development could result in "programmatic" changes via alterations in gene expression or gene imprinting that may result in functional deficits that become apparent later in life. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by excessive deposits of aggregated beta-amyloid (Abeta) peptides, which are snippets of the beta-amyloid precursor protein (APP). The predominantly sporadic nature of AD suggests that the environment must play a role in neurodegeneration. To examine latent responses to an environmental agent, we exposed rodents to lead and monitored the lifetime expression of the APP gene. We observed that APP mRNA expression was transiently induced in neonates, but exhibited a delayed overexpression 20 months after exposure to Pb had ceased. This upregulation in APP mRNA expression was commensurate with a rise in activity of the transcription factor Sp1, one of the regulators of the APP gene. Furthermore, the increase in APP gene expression in old age was accompanied by an elevation in APP and its amyloidogenic Abeta product. In contrast, APP expression, Sp1 activity, as well as APP and Abeta protein levels were unresponsive to Pb exposure during old age. These data suggested that environmental influences occurring during brain development predetermined the expression and regulation of APP later in life, potentially altering the course of amyloidogenesis. PMID: 156736613. http://tinyurl.com/38h92mAlzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for ADThe Journal of Neuroscience, January 2, 2008, 28(1):3-9; doi:10.1523/JNEUROSCI.4405-07.2008Jinfang Wu,1 Md. Riyaz Basha,1 Brock,1 P. ,2 Cardozo-Pelaez,2 A. McPherson,3 Harry,3 Deborah C. Rice,4 Maloney,5 Demao Chen,5 Debomoy K. Lahiri,5 and Nasser H. Zawia11Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, 2Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, University of Montana, Missoula, Montana 59812, 3National Institutes of Health, Research Triangle Park, North Carolina 27709, 4Maine Department of Health and Human Services, Augusta, Maine 04333, and 5Laboratory for Molecular Neurogenetics, Institute for Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202Correspondence should be addressed to Dr. Nasser H. Zawia, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881. Email: nzawia{at}uri.eduThe sporadic nature of Alzheimer's disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic â-amyloid (Aâ) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (â-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Aâ staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD.

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