(84af) Developmental Pb Exposure Increases AD Risk Via Altered Intracellular Ca2+ Homeostasis in hiPSC-Derived Cortical Neurons

Background: 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 a strong association 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.

Objective: In this work, we used human iPSC-derived cortical neurons as a model system to study the effects of Pb exposure on developing and maturing human cortical neurons.

Methods: Neural progenitor cells induced from human iPSC were exposed to 0, 15 and 50 ppb of lead which were further differentiated into mature cortical neurons. RNA-sequencing and immunofluorescence were used to study the changes in transcriptome and protein expression. ELISA assays for β-amyloid and FRET imaging on tau biosensors were used to assess the AD-like phenotype related to developmental Pb exposure.

Results: Neural progenitor cells (NPC) were exposed to environmentally relevant levels of Pb at 15 and 50 ppb for 48 h, differentiated into cortical neurons and assessed for maturity and AD-like pathogenesis. Although developmental Pb exposure does not significantly alter the differentiation process, we observed altered neuronal morphology including neurite length and synapse density. Furthermore, mature neurons with prior Pb exposure showed significantly elevated intracellular calcium concentration, as well as an altered epigenetic landscapes and transcriptomic profile. Comparison of transcriptomic data between treated and unexposed cells revealed differentially expressed genes enriched in calcium-homeostasis regulating processes such as GRIN1 and CAMK2B which we further verified using immunofluorescence. Developmental Pb exposure also leads to elevated phosphorylated tau in treated neurons and secreted tau aggregates and Aβ 42 in cell culture medium along with other AD transcriptomic markers.

Conclusion: 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.