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.

The sporadic nature in over 90% of Alzheimer’s disease (AD) cases, the differential susceptibility and course of illness, and latent onset of the disease suggest involvement of an environmental component in the etiology of late onset AD (LOAD). Recent reports from our lab have demonstrated that molecular alterations favor abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with infantile lead (Pb) exposure (Bihaqi and Zawia, 2013). Here we report that developmental Pb exposure results in elevation of protein and mRNA levels of tau in aged mice. Western blot analysis revealed aberrant site-specific tau hyperphosphorylation accompanied by elevated cyclin dependent kinase 5 (CDK5) levels in aged mice with prior Pb exposure. Mice with developmental Pb exposure also displayed altered protein ratio of p35/p25 with more Serine/Threonine phosphatase activity at old age. These changes favored increase in tau phosphorylation, thus providing evidence that neurodegenerative diseases may be in part due to environmental influences that occur during development.