The beginnings of late onset Alzheimer's disease (LOAD) are still unknown; however, the progressive and latent nature of neurodegeneration suggests that the triggering event occurs earlier in life. Aging primates exposed to lead (Pb) as infants exhibited an overexpression of the amyloid-β protein precursor (AβPP), amyloid-β (Aβ) and enhanced pathologic neurodegeneration. In this study, we measured the latent expression of a wide array of brain-specific genes and explored whether epigenetic pathways mediated such latent molecular and pathological changes. We analyzed the levels of proteins associated with DNA methylation, i.e., DNA methyltransferase 1 (Dnmt1), DNA methyltransferase3a (Dnmt3a), methyl-CpG binding protein-2 (MeCP2) and those involved in histone modifications (acetylated and methylated histones). We monitored the expression profiles of these intermediates across the lifespan and analyzed their levels in 23-year-old primate brains exposed to Pb as infants. Developmental Pb exposure altered the gene expression of the arrayed genes, which were predominately repressed, with fewer upregulated genes. The latent induction and repression of genes was accompanied by a significant decrease in the protein levels of Dnmts, MeCP2, and proteins involved in histone modifications. The attenuation of DNA methylation enzymes is consistent with hypomethylating effects, which promote upregulation of the genes, while the alterations in the histone modifiers are associated with the repression of genes. Hence, we deduce that early life exposure to Pb can reprogram gene expression resulting in both upregulation and down-regulation of genes through alternate epigenetic pathways contributing to an enhancement in neurodegeneration in old age.

Background Early-life lead (Pb) exposure induces overexpression of the amyloid beta precursor protein and its amyloid beta product in older rats and primates. We exposed rodents to Pb during different life span periods and examined cognitive function in old age and its impact on biomarkers associated with Alzheimer’s disease (AD). Methods Morris, Y, and the elevated plus mazes were used. Western blot, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay were used to study the levels of AD biomarkers. Results Cognitive impairment was observed in mice exposed as infants but not as adults. Overexpression of AD-related genes (amyloid beta precursor protein and β-site amyloid precursor protein cleaving enzyme 1) and their products, as well as their transcriptional regulator—specificity protein 1 (Sp1)—occurred only in older mice with developmental exposure to Pb. Conclusions A window of vulnerability to Pb neurotoxicity exists in the developing brain that can influence AD pathogenesis and cognitive decline in old age.

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Late Onset Alzheimer Disease (LOAD) constitutes the majority of AD cases (~90%). Amyloidosis and tau pathology, which are present in AD brains, appear to be sporadic in nature. We have previously shown that infantile lead (Pb) exposure is associated with a change in the expression and regulation of the amyloid precursor protein (APP) and its beta amyloid (Aβ) products in old age. Here we report that infantile Pb exposure elevated the mRNA and protein levels of tau as well as its transcriptional regulators namely specificity protein 1 and 3 (Sp1 and Sp3) in aged primates. These changes were also accompanied by an enhancement in site-specific tau phosphorylation as well as an increase in the mRNA and protein levels of cyclin dependent kinase 5 (cdk5). There was also a change in the protein ratio of p35/p25 with more Serine/Threonine phosphatase activity present in aged primates exposed to Pb as infants. These molecular alterations favored abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with prior Pb exposure. These findings provide more evidence that neurodegenerative diseases may be products of environmental influences that occur during the development.