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The Journal of Neuroscience, January 2, 2008, 28(1):3-9; doi:10.1523/JNEUROSCI.4405-07.2008

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Neurobiology of Disease
Alzheimer'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 AD

Jinfang Wu,¹ Md. Riyaz Basha,¹ Brian Brock,¹ David P. Cox,² Fernando Cardozo-Pelaez,² Christopher A. McPherson,³ Jean Harry,³ Deborah C. Rice,⁴ Bryan Maloney,⁵ Demao Chen,⁵ Debomoy K. Lahiri,⁵ and Nasser H. Zawia¹

¹Department 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 46202

Correspondence 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.edu

The 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 β-amyloid (Aβ) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (β-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 Aβ 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.

Key words: amyloidogenesis; development; environmental exposure; Pb; epigenetic regulation; transcription factor

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Received Sept. 26, 2007; revised Oct. 31, 2007; accepted Nov. 1, 2007.

Correspondence 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.edu

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