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

Abstract

BackgroundAlzheimer'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.MethodsThis 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 Aβ1–42 neurotoxicity. In vivo experiments on AD mice evaluated the effects of miR‐137‐5p on cognition, Aβ1–42 deposition, Tau hyperphosphorylation, and neuronal apoptosis, as well as its influence on USP30 levels.ResultsIt was discovered that miR‐137‐5p mimics efficiently counteract Aβ1–42 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 Aβ1–42 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.ConclusionOur 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.

Potential Application of MicroRNAs and Some Other Molecular Biomarkers in Alzheimer’s Disease

“…In the study conducted by Jiang et al [ 62 ], the focus was on investigating the association between miRNA-137-5p and the USP30 deubiquitinase, which plays a role in mitophagy. The research demonstrated that miRNA-137-5p contributes to alleviating symptoms of AD by downregulating USP30 levels in both mouse (C57BL/6J) and cell (SH-SY5Y) models [ 62 ]. In the study, mice were surgically sectioned and injected into the hippocampal area.…”

“…The AD+mmu-agomiR-137-5p group received 1.5 µL of antagomir at a concentration of 100 µM, while the AD+mmu-agomiR-137-5p+USP30 group received 1.5 µL of antagomir at a concentration of 100 µM along with 2 µL of lentivirus. Furthermore, the researchers established a link between miRNA-137-5p and Aβ-associated neurotoxicity [ 62 ]. It was found that miRNA-137-5p mitigates this neurotoxicity by targeting USP30 [ 62 , 63 ].…”

“…Furthermore, the researchers established a link between miRNA-137-5p and Aβ-associated neurotoxicity [ 62 ]. It was found that miRNA-137-5p mitigates this neurotoxicity by targeting USP30 [ 62 , 63 ].…”