miRNA-137-5p improves spatial memory and cognition in Alzheimer's mice by targeting ubiquitin-specific peptidase 30.

BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder causing progressive dementia. Research suggests that microRNAs (miRNAs) could serve as biomarkers and therapeutic targets for AD. Reduced levels of miR-137 have been observed in the brains of AD patients, but its specific role and downstream mechanisms remain unclear. This study sought to examine the therapeutic potential of miR-137-5p agomir in alleviating cognitive dysfunction induced in AD models and explore its potential mechanisms. METHODS: This study utilized bioinformatic analysis and a dual-luciferase reporter assay to investigate the relationship between miR-137-5p and ubiquitin-specific peptidase 30 (USP30). In vitro experiments were conducted using SH-SY5Y cells to assess the impact of miR-137-5p on Aß1-42 neurotoxicity. In vivo experiments on AD mice evaluated the effects of miR-137-5p on cognition, Aß1-42 deposition, Tau hyperphosphorylation, and neuronal apoptosis, as well as its influence on USP30 levels. RESULTS: It was discovered that miR-137-5p mimics efficiently counteract Aß1-42 neurotoxicity in SH-SY5Y cells, a protective effect that is negated by USP30 overexpression. In vivo experiments demonstrated that miR-137-5p enhances the cognition and mobility of AD mice, significantly reducing Aß1-42 deposition, Tau hyperphosphorylation, and neuronal apoptosis within the hippocampus and cortex regions. Mechanistically, miR-137-5p significantly suppresses USP30 levels in mice, though USP30 overexpression partially buffers against miR-137-5p-induced AD symptom improvement. CONCLUSION: Our study proposes that miR-137-5p, by instigating the downregulation of USP30, has the potential to act as a novel and promising therapeutic target for AD.

TGF-ß promotes glioma cell growth via activating Nodal expression through Smad and ERK1/2 pathways.

While there were certain studies focusing on the mechanism of TGF-ß promoting the growth of glioma cells, the present work revealed another novel mechanism that TGF-ß may promote glioma cell growth via enhancing Nodal expression. Our results showed that Nodal expression was significantly upregulated in glioma cells when TGF-ß was added, whereas the TGF-ß-induced Nodal expression was evidently inhibited by transfection Smad2 or Smad3 siRNAs, and the suppression was especially significant when the Smad3 was downregulated. Another, the attenuation of TGF-ß-induced Nodal expression was observed with blockade of the ERK1/2 pathway also. Further detection of the proliferation, apoptosis, and invasion of glioma cells indicated that Nodal overexpression promoted the proliferation and invasion of tumor cells and inhibited their apoptosis, resembling the effect of TGF-ß addition. Downregulation of Nodal expression via transfection Nodal-specific siRNA in the presence of TGF-ß weakened the promoting effect of the latter on glioma cells growth, and transfecting Nodal siRNA alone in the absence of exogenous TGF-ß more profoundly inhibited the growth of glioma cells. These results demonstrated that while both TGF-ß and Nodal promoted glioma cells growth, the former might exert such effect by enhancing Nodal expression, which may form a new target for glioma therapy.