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

Abstract

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 b-amyloid 1-42 (Ab1-42) 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 Ab1-42. 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 Ab1-42-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.

Defective mitophagy and the etiopathogenesis of Alzheimer’s disease

“…PINK1 overexpression enhances autophagy signaling by activating autophagy receptors OPTN and NDP52, thereby promoting clearance of damaged mitochondria, reducing oxidative stress, and alleviating synaptic damage and cognitive decline in APP/PS1 mice [ 107 ]. Studies on the role of non-transcribed microRNAs in mitophagy reveal that inhibiting miR-204 expression can efficiently inhibit AD progression by improving mitophagy [ 108 ].…”

The regulatory roles of microRNAs toward pathogenesis and treatments in Huntington's disease

“…In addition, miR-338 targets to cytochrome-c oxidase subunit 4I1 (COX4I1) to regulate mitochondrial ATP production in brains [ 59 ]. Furthermore, miR-204 is upregulated to target transient receptor potential mucolipin-1 (TRPML1) to damage mitochondrial membrane potential and ATP production in AD, and suppression of miR-204 rescues those mitochondrial damages and reactive oxygen species (ROS) productions through upregulation of TRPML1 [ 60 ]. These results indicate brain-enriched miRNAs, such as miR-137, miR-338 and miR-204, play critical roles to maintain mitochondrial biogenesis and biofunctions during brain development, and unbalance of these miRNA regulations leads to the progression of neuronal diseases (Fig.…”

[18F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer’s disease pathology in APP/PS1 mice

“…The fluorescent images revealed that DHE was localized to the cytoplasm of neurons in the APP/PS1 brain only (Fig. 4a, b), which may represent Aβ-induced mitochondrial ROS [12, 48]. DHE was also frequently found in aggregated microglia in the APP/PS1 brain.…”