Gastrodin ameliorates synaptic impairment, mitochondrial dysfunction and oxidative stress in N2a/APP cells.

Alzheimer's disease is characterized by abnormal ß-amyloid and tau accumulation, mitochondrial dysfunction, oxidative stress, and synaptic dysfunction. Here, we aimed to assess the mechanisms and signalling pathways in the neuroprotective effect of gastrodin, a phenolic glycoside, on murine neuroblastoma N2a cells expressing human Swedish mutant APP (N2a/APP). We found that gastrodin increased the levels of presynaptic-SNAP, synaptophysin, and postsynaptic-PSD95 and reduced phospho-tau Ser396, APP and Aß1-42 levels in N2a/APP cells. Gastrodin treatment reduced reactive oxygen species generation, lipid peroxidation, mitochondrial fragmentation and DNA oxidation; restored mitochondrial membrane potential and intracellular ATP production. Upregulated phospho-GSK-3ß and reduced phospho-ERK and phospho-JNK were involved in the protective effect of gastrodin. In conclusion, we demonstrated the neuroprotective effect of gastrodin in the N2a/APP cell line by ameliorating the impairment on synaptic and mitochondrial function, reducing tau phosphorylation, Aß1-42 levels as well as reactive oxygen species generation. These results provide new mechanistic insights into the potential effect of gastrodin in the treatment of Alzheimer's disease.

NRF2 Deficiency Promotes Ferroptosis of Astrocytes Mediated by Oxidative Stress in Alzheimer's Disease.

Oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD), which is linked to reactive oxygen species (ROS), lipid peroxidation, and neurotoxicity. Emerging evidence suggests a role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a major source of antioxidant response elements in AD. The molecular mechanism of oxidative stress and ferroptosis in astrocytes in AD is not yet fully understood. Here, we aimed to investigate the mechanism by which Nrf2 regulates the ferroptosis of astrocytes in AD. We found decreased expression of Nrf2 and upregulated expression of the ROS marker NADPH oxidase 4 (NOX4) in the frontal cortex from patients with AD and in the cortex of 3×Tg mice compared to wildtype mice. We demonstrated that Nrf2 deficiency led to ferroptosis-dependent oxidative stress-induced ROS with downregulated heme oxygenase-1 and glutathione peroxidase 4 and upregulated cystine glutamate expression. Moreover, Nrf2 deficiency increased lipid peroxidation, DNA oxidation, and mitochondrial fragmentation in mouse astrocytes (mAS, M1800-57). In conclusion, these results suggest that Nrf2 deficiency promotes ferroptosis of astrocytes involving oxidative stress in AD.