Acrolein-Induced Alterations in Morphology and Stress Resilience in hiPSC-Derived Cortical Neurons

Acrolein, an α,β-unsaturated aldehyde and reactive oxygen species (ROS), originates from both endogenous mechanisms, such as lipid peroxidation, and exogenous sources, including the decomposition of organic matter. Elevated levels of acrolein are detected in the brains of individuals with Alzheimer's and Parkinson's diseases, as well as those with traumatic brain or spinal cord injuries. Environmental exposure, including smoking and industrial emissions, further contribute to acrolein accumulation. Despite their recognized immediate neurotoxic effects, the chronic implications on neurodegeneration remain elusive. To elucidate these effects, human induced pluripotent stem cell (hiPSC)-derived human cortical neurons (∼Day 60 postdifferentiation) were subjected to 0, 1, and 10 μM concentrations of acrolein for 2 days following a nonexposure relaxation period (7 days) to assess the persistence of the resulting phenotypes. Immunofluorescence and calcium imaging demonstrated sustained alterations in the synaptic density and neuronal activity in acrolein-exposed differentiated neurons. Moreover, a persistent and dose-dependent neuronal hyperactivity was identified through microelectrode array analysis. Acrolein exposure also precipitated sustained elevations in Alzheimer's Disease-related phosphorylated Tau (p-tau) pathology and mitochondrial stress, along with diminished cellular resilience to subsequent stressors. Collectively, these findings support a persistent neurotoxic effect of acrolein, highlighting its potential implications for neurodegenerative disorders.