miR-204 silencing reduces mitochondrial autophagy and ROS production in a murine AD model via the TRPML1-activated STAT3 pathway

• Main Authors: Lu Zhang, Yu Fang, Xinyu Zhao, Yake Zheng, Yunqing Ma, Shuang Li, Zhi Huang, Lihao Li
• Format: Article
• Language: English
• Published: Elsevier 2021-06-01
• Series: Molecular Therapy: Nucleic Acids
• Subjects: Alzheimer’s disease; signal transducer and activator of transcription 3; microRNA-204; transient receptor potential mucolipin-1; mitochondrial autophagy; reactive oxygen species
• Online Access: http://www.sciencedirect.com/science/article/pii/S2162253121000457

Mitochondrial dysfunction is an early feature of Alzheimer’s disease (AD), whereby accumulation of damaged mitochondria in conjunction with impaired mitophagy contributes to neurodegeneration. Various non-transcribed microRNAs (miRNAs) are involved in this process. In the present study, we aimed to decipher the participation of miR-204 in a murine AD model. Primary hippocampal neurons were isolated from mice and treated with β-amyloid 1-42 (Aβ1-42) to establish a cell model of AD. Dichloro-dihydro-fluorescein diacetate and dihydrorhodamine 123 staining assays were performed to measure total reactive oxygen species (ROS) and mitochondrial ROS production in neurons, and MitoSOX staining was done to analyze mitochondrial ROS production in hippocampus. Furthermore, mitochondrial autophagy was observed in hippocampus from amyloid precursor protein/pesenilin-1 AD modeled mice, and their cognitive function was assessed by Morris water maze. Mitochondrial damage, ROS production, and mitochondrial autophagy were observed in AD cell model induced by Aβ1-42. In AD, signal transducer and activator of transcription 3 (STAT3) and transient receptor potential mucolipin-1 (TRPML1) expression was downregulated, although miR-204 expression was upregulated. TRPML1 overexpression, downregulation of miR-204, or STAT3 pathway activation reduced the Aβ1-42-induced mitochondrial damage, along with ROS production and mitochondrial autophagy in vivo and in vitro. Silencing of miR-204 could upregulate TRPML1 expression, thus suppressing ROS production and mitochondrial autophagy in AD through STAT3 pathway.