In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been sho...In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.e B-GFAP-sh PTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-sh PTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment.展开更多
Background:Alzheimer’sdisease(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 ...Background:Alzheimer’sdisease(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 down stream 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-l uciferase 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.Results:It 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-i nduced 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.展开更多
基金supported by the National Natural Science Foundation of China,No.82071418the Natural Science Foundation of Fujian Province,No.2020J01612 (both to EH)。
文摘In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.e B-GFAP-sh PTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-sh PTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment.
基金Liaoning Province Science and Technology Project(grant/award number:2019-BS-221)Shenyang Science and Technology Project(grant/award number:19-112-4-040)。
文摘Background:Alzheimer’sdisease(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 down stream 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-l uciferase 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.Results:It 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-i nduced 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.
