Tangeretin protects against Aβ1-42-induced toxicity and exploring mitochondria-lysosome interactions in HT22 cells

Tangeretin, a flavonoid from Citri Reticulatae Pericarpium, is known for its neuroprotective effects, but the mechanisms are not fully understood. Alzheimer's disease, a leading neurodegenerative disorder, characterized by amyloid-beta (Aβ) accumulation, represents a significant therapeutic challenge. This study investigates the protective effects of tangeretin against Aβ1-42-induced neurotoxicity using HT22 cells and zebrafish larvae as experimental models. Tangeretin mitigated Aβ_1-42-induced cytotoxicity, as evidenced by enhanced cell viability and reduced apoptosis. Tangeretin treatment mitigated Aβ_1-42-induced cytotoxicity in HT22 cells, as evidenced by enhanced cell viability and reduced apoptosis. Mechanistically, tangeretin ameliorated mitochondrial dysfunction by reducing mitochondrial fragmentation, decreasing donut-shaped mitochondria, restoring mitochondrial membrane potential, and attenuating reactive oxygen species (ROS) production. Moreover, tangeretin modulated mitochondria-lysosome interactions by promoting mitophagy and normalizing the prolonged mitochondria-lysosome contact induced by Aβ_1-42. In zebrafish larvae, Aβ_1-42 exposure resulted in developmental malformations, including pericardial and yolk sac edema, elevated ROS levels, increased apoptosis, and impaired neurodevelopment. Tangeretin effectively counteracted these deficits, as revealed by live imaging, supporting its neuroprotective role observed in cellular models. Collectively, our study suggests that tangeretin may serve as a promising protective agent against Aβ_1-42-induced neurotoxicity.