Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 1, Pages 3-9Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4405-07.2008
Keywords
amyloidogenesis; development; environmental exposure; Pb; epigenetic regulation; transcription factor
Categories
Funding
- Intramural NIH HHS [Z01 ES021164-11] Funding Source: Medline
- NCRR NIH HHS [P20 RR016457, P20RR016457] Funding Source: Medline
- NIA NIH HHS [R15 AG023604, R03 AG027246, R0AG18379, 1R15AG023604-01, R0AG18884, R01 AG018884, AG027246, R01 AG018379] Funding Source: Medline
- NIEHS NIH HHS [ES013022, R21 ES013022] Funding Source: Medline
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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 beta-amyloid (A beta) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (beta- 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 A beta 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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