通过抑制 TBC1D5 表达增强 Rab7 活性可改善阿尔茨海默病模型中的丝裂吞噬功能

IF 3.4 3区 医学 Q2 NEUROSCIENCES Journal of Alzheimer's Disease Pub Date : 2024-06-01 DOI:10.3233/jad-231300
Xiao Liang, Yangyang Wang, Siyu Li, Jianing Fan, Fanlin Zhou, Xiaoju Li, Shijie Li, Yu Li
{"title":"通过抑制 TBC1D5 表达增强 Rab7 活性可改善阿尔茨海默病模型中的丝裂吞噬功能","authors":"Xiao Liang, Yangyang Wang, Siyu Li, Jianing Fan, Fanlin Zhou, Xiaoju Li, Shijie Li, Yu Li","doi":"10.3233/jad-231300","DOIUrl":null,"url":null,"abstract":"Background: Mitochondrial dysfunction exists in Alzheimer’s disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. Objective: To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. Methods: Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-β secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. Results: Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. Conclusions: Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy.","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":null,"pages":null},"PeriodicalIF":3.4000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Enhancing Rab7 Activity by Inhibiting TBC1D5 Expression Improves Mitophagy in Alzheimer’s Disease Models\",\"authors\":\"Xiao Liang, Yangyang Wang, Siyu Li, Jianing Fan, Fanlin Zhou, Xiaoju Li, Shijie Li, Yu Li\",\"doi\":\"10.3233/jad-231300\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Background: Mitochondrial dysfunction exists in Alzheimer’s disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. Objective: To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. Methods: Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-β secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. Results: Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. Conclusions: Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy.\",\"PeriodicalId\":14929,\"journal\":{\"name\":\"Journal of Alzheimer's Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2024-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Alzheimer's Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3233/jad-231300\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Alzheimer's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3233/jad-231300","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

摘要

背景:阿尔茨海默病(AD)大脑中存在线粒体功能障碍,受损的线粒体需要通过有丝分裂来清除。小 GTPase Rab7 调节线粒体和溶酶体的融合,而 TBC1D5 则抑制 Rab7 的活化。然而,TBC1D5对Rab7活性的调节是否能改善有丝分裂并抑制AD的进展尚不清楚。目的探讨TBC1D5在有丝分裂中的作用及其对Rab7的调控机制,以及激活有丝分裂是否能抑制AD的进展。研究方法:采用Western荧光法检测有丝分裂:通过Western印迹和免疫荧光检测有丝分裂。采用 pCMV-Mito-AT1.03 检测细胞 ATP。用 ELISA 检测 AD 细胞分泌的淀粉样蛋白-β。共免疫沉淀用于研究目标蛋白的结合伙伴。应用高尔基体-毒素染色法观察小鼠神经元的形态。进行了莫里斯水迷宫测试和Y迷宫测试以评估小鼠的空间学习和记忆能力,并进行了开阔地测试以评估实验动物的运动功能和焦虑样表型。实验结果AD模型的线粒体形态受损,TBC1D5高表达。敲除TBC1D5可增加活性Rab7的表达,促进溶酶体和自噬体的融合,从而改善线粒体吞噬,改善AD小鼠海马神经元的形态和行为障碍。结论敲除TBC1D5能提高Rab7的活性,促进自噬体和溶酶体的融合。我们的研究为针对有丝分裂的AD治疗提供了新的可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Enhancing Rab7 Activity by Inhibiting TBC1D5 Expression Improves Mitophagy in Alzheimer’s Disease Models
Background: Mitochondrial dysfunction exists in Alzheimer’s disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. Objective: To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. Methods: Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-β secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. Results: Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. Conclusions: Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Alzheimer's Disease
Journal of Alzheimer's Disease 医学-神经科学
CiteScore
6.40
自引率
7.50%
发文量
1327
审稿时长
2 months
期刊介绍: The Journal of Alzheimer''s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer''s disease. The journal publishes research reports, reviews, short communications, hypotheses, ethics reviews, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer''s disease.
期刊最新文献
Assessing palliative care needs in patients with dementia: A cross-sectional analysis of an predominantly oldest-old population from a geriatric memory clinic. Tri-culture modeling of neuroinflammation, neurodegeneration, and neuroprotection. Real-world assessment of caregiver preference and compliance to treatment with twice-weekly versus daily rivastigmine patches in Alzheimer's disease. A call for globally responsive screening materials to account for heterogeneity in dementia syndromes. Primary cortical cell tri-culture to study effects of amyloid-β on microglia function and neuroinflammatory response.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1