Diminazene attenuates astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in Alzheimer's Disease Model.

Abstract

PURPOSE: Diminazene (DIZE), an agonist of the Ang-(1-7) system, has been proven to suppress astrocytic neuroinflammatory responses in Alzheimer's disease (AD). NADPH oxidase 4 (NOX4) is abundantly expressed in astrocytes and critically mediates oxidative stress damage and ferroptosis. However, the mode of DIZE in AD-related NOX4 overactivation and ferroptosis remains to be revealed. METHODS: Male APP/PS1 mice received DIZE and the ferroptosis inhibitor Liproxstatin-1 (LIP) treatment. Behavioral tests, Nissl staining, Western blotting, ELISA and immunofluorescence were performed to evaluate the effects of DIZE on neuronal loss, synaptic damage, inflammation and iron accumulation. Astrocytes from APP/PS1 mice were underwent high-throughput miRNA sequencing to identity the most differentially expressed miRNAs after DIZE administration. Subsequently, the role of this miRNA in DIZE's anti-ferroptosis impact within primary astrocytes was explored. RESULTS: DIZE markedly reduced iron accumulation while lowering oxidative stress and inflammation in APP/PS1 mice. Simultaneously, DIZE significantly mitigated cognitive deficits and synaptic injury in APP/PS1 mice. DIZE suppressed the expression level of NOX4 and upregulated miR-10b-3p. Importantly, miR-10b-3p levels were notably elevated in astrocytes of APP/PS1 mice administered DIZE, targeting the NOX4 protein. Inhibition of miR-10b-3p expression significantly reversed the therapeutic effect of DIZE. CONCLUSION: These findings indicate that DIZE suppresses astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in AD model.