Recommended Citation
Xie J, Wu S, Szadowski H, Min S, Yang Y, Bowman AB, Rochet JC, Freeman JL, Yuan C. Developmental Pb exposure increases AD risk via altered intracellular Ca2+ homeostasis in hiPSC-derived cortical neurons. J Biol Chem. 2023 Aug;299(8):105023. doi: 10.1016/j.jbc.2023.105023
DOI
https://doi.org/10.1016/j.jbc.2023.105023
Date of this Version
7-7-2023
Keywords
Alzheimer’s disease; Pb exposure; cortical neuron; hiPSC; neurodegenerative disease.
Abstract
Exposure to environmental chemicals such as lead (Pb) during vulnerable developmental periods can result in adverse health outcomes later in life. Human cohort studies have demonstrated associations between developmental Pb exposure and Alzheimer's disease (AD) onset in later life which were further corroborated by findings from animal studies. The molecular pathway linking developmental Pb exposure and increased AD risk, however, remains elusive. In this work, we used human iPSC-derived cortical neurons as a model system to study the effects of Pb exposure on AD-like pathogenesis in human cortical neurons. We exposed neural progenitor cells derived from human iPSC to 0, 15, and 50 ppb Pb for 48 h, removed Pb-containing medium, and further differentiated them into cortical neurons. Immunofluorescence, Western blotting, RNA-sequencing, ELISA, and FRET reporter cell lines were used to determine changes in AD-like pathogenesis in differentiated cortical neurons. Exposing neural progenitor cells to low-dose Pb, mimicking a developmental exposure, can result in altered neurite morphology. Differentiated neurons exhibit altered calcium homeostasis, synaptic plasticity, and epigenetic landscape along with elevated AD-like pathogenesis markers, including phosphorylated tau, tau aggregates, and Aβ42/40. Collectively, our findings provide an evidence base for Ca dysregulation caused by developmental Pb exposure as a plausible molecular mechanism accounting for increased AD risk in populations with developmental Pb exposure.
Comments
This is the published version of the Xie J, Wu S, Szadowski H, Min S, Yang Y, Bowman AB, Rochet JC, Freeman JL, Yuan C. Developmental Pb exposure increases AD risk via altered intracellular Ca2+ homeostasis in hiPSC-derived cortical neurons. J Biol Chem. 2023 Aug;299(8):105023. doi: 10.1016/j.jbc.2023.105023