Disruption of cerebral cholesterol homeostasis by PS-NPs: astrocytic endoplasmic reticulum stress

Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, Cholesterol in the brain is primarily self-synthesized by astrocytes. However, limited research has been conducted on the effects of polystyrene nanoplastic (PS-NPs) on intracranial Cholesterol metabolic pathways. In this study, we exposed whole-brain organoids (WBOs) to PS-NPs and identified significant changes in endoplasmic reticulum stress and Cholesterol biosynthesis pathways through whole-transcriptome Sequencing. To investigate potential mechanisms of altered Cholesterol pathways, we constructed a Transwell neuronal-astrocyte co-culture model. Results demonstrated that PS-NPs induced significant endoplasmic reticulum stress in astrocytes, specifically manifested by elevated levels of ATF4 and CHOP, along with increased Autophagy indicated by the elevated LC3-II/I ratio. PS-NPs significantly inhibited the Akt/ACLY pathway of Cholesterol biosynthesis, leading to marked reductions in acetyl-CoA and Cholesterol within astrocytes (P < 0.05). In addition, PS-NPs led to a significant reduction of Apolipoprotein APOE, which hindered Cholesterol transport and ultimately inhibited synaptin (SYN) formation. In summary, PS-NPs induce endoplasmic reticulum stress and Autophagy in astrocytes, impair Cholesterol de novo synthesis and apolipoprotein-mediated transport, ultimately inhibiting neuronal synaptogenesis. Furthermore, specific inhibition of ERs restored Cholesterol synthesis in astrocytes and neuronal synapses. This study demonstrates that PS-NPs produce neurotoxic effects by affecting Cholesterol homeostasis in the brain.