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

Abstract

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

Variations of transcript profiles between sea otters Enhydra lutris from Prince William Sound, Alaska, and clinically normal reference otters

“…As a result of this keystone function, analysis of mRNA can provide information not only about genetic potential but also about dynamic changes in the functional state of an organism. In fact, mRNA levels closely approximate functional protein levels, and specific changes in mRNA have been identified following heat shock, drug treatment, and metabolic and disease states (Wu et al 2008, Miller et al 2011. The utility of the methodology proposed in our study relies on the assumption that oil-induced sublethal pathology in sea otters is accompanied by predictable and specific changes in gene transcription.…”

Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition

“…In rodent and rabbit models of Alzheimer's disease on cholesterolrich diets, trace iron intake may be a critical variable (70). Lead can also promote later formation of amyloid deposits in monkeys (71). However, none of the rodent or primate models has shown the extensive neuronal loss characteristic of human Alzheimer's disease by early clinical stages.…”

Timing is everything

“…36,37 In primates, early exposure to lead (Pb) results in decreased DNA methyltransferase activity in the brain even 23 years later, suggestive of decreased DNA methylation, though this remains to be directly tested. 38 Given the emerging weight of evidence linking developmental toxicant exposures to later disease states in animal models via methylation, unraveling these potential human health effects is particularly crucial.…”