Infantile postnatal exposure to lead (Pb) enhances tau expression in the cerebral cortex of aged mice: Relevance to AD

Abstract

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.

Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model

“…The findings from this current study illustrated that Pb indeed has an effect on the human tau gene which occurs within a stage-specific developmental window and then normalized by adulthood. These observations are consistent with numerous studies reported by our group on the impact of developmental Pb exposure and gene expression and more recently shown to occur for tau (Bihaqi et al, 2014). The latent effects of elevated tau levels in late life seen in the wild-type mice are possibly being established and further aging of these mice would be expected to reveal a delayed upregulation in this biomarker in old age.…”

“…Extant findings for wild-type mice have provided evidence that developmental Pb exposure has an effect on tau, its kinase's and phospho-tau (Bihaqi et al, 2014). The expressed hypothesis of this study was focused on identifying the responsiveness of the human tau transgene to an environmental exposure.…”

“…Previous studies have shown postnatal exposure in wild-type mice increases levels of tau, phosphorylated tau, and its related enzymes (Bihaqi et al, 2014). We tested to see the same pattern within the transgenic mouse model between PND 20-60.…”

“…One group of mice was exposed to Pb during the first 20 days of postnatal life according to the protocol we have published previously (Bihaqi et al, 2014). Mice in the second cohort were not exposed to Pb and served as controls.…”

“…These behavioral deficits correlated with the changes in the protein and gene expression levels of tau, phosphorylated tau, related enzymes and transcription factors (Bihaqi et al, 2014; Bihaqi and Zawia, 2013). More recently we discovered that epigenetic mediators such as microRNA may paly a role in mediating these changes in gene expression (Masoud et al, 2016).…”