Gene therapy for Alzheimer's disease by viral vector-mediated neprilysin, an Aβ-degrading enzyme, gene transfer
通过病毒载体介导的脑啡肽酶(一种 Aβ 降解酶)、基因转移对阿尔茨海默病进行基因治疗
基本信息
- 批准号:14370762
- 负责人:
- 金额:$ 9.6万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2002
- 资助国家:日本
- 起止时间:2002 至 2003
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Accumulation of amyloid-β peptide (Aβ) in the brain is a triggering event leading to the pathological cascade of Alzheimer's disease (AD). It is necessary for therapy and prevention of AD to treat a great backlog of Aβ clearance. Neprilysin is a rate-limiting peptidase, which participates in Aβ degradation in brain. As demonstrated by reverse genetics, the disruption of neprilysin gene causes elevation of the endogenous Aβ levels in mouse brain in a gene-close-dependent manner. Therefore, reduction of neprilysin activity will contribute to Aβ deposition and thus to AD development. Recent evidence that expression levels of neprilysin were reduced in the hippocampus of sporadic AD patients and aged laboratory mice suggests a close association of neprilysin with the etiology and pathogenesis of AD. We attempted to express neprilysin, an Aβ-degrading enzyme, in the hippocampal formation of mice in vivo by recombinant adeno-associated virus-mediated gene transfer. Neprilysin expressed by th … More e gene transfer was axonally transported to presynaptic sites through afferent projections of neuronal circuits. This gene transfer abolished the increase in Aβ levels in the hippocampal formations of neprilysin-deficient mice, and also reduced the increase in young mutant amyloid precursor protein (APP) transgenic mice. In the latter case, Aβ levels in the hippocampal formation contralateral to the vector-injected side were also significantly reduced as a result of transport of neprilysin from the ipsilateral side. Furthermore, amyloid deposition in aged mutant APP transgenic mice was remarkably decelerated. These results indicate that presynaptic localization of neprilysin contributes to efficient and extensive clearance of Aβ and protects synapses from synaptic toxicity by Aβ, and that Lip-regulation of neprilysin activity would be a promising strategy for therapy and prevention of AD. In addition, these results suggest that gene therapy to directly introduce an Aβ-degradler into the brain may have potential as a treatment for AD. Less
淀粉样蛋白-β肽(a β)在大脑中的积累是导致阿尔茨海默病(AD)病理级联的触发事件。治疗大量积压的a β清除对于治疗和预防AD是必要的。Neprilysin是一种限速肽酶,参与脑内a β的降解。反向遗传学研究表明,neprilysin基因的破坏导致小鼠大脑内源性a β水平以基因密切依赖的方式升高。因此,neprilysin活性的降低将有助于Aβ沉积,从而促进AD的发展。最近有证据表明,散发性阿尔茨海默病患者和老年实验小鼠海马中neprilysin的表达水平降低,表明neprilysin与阿尔茨海默病的病因和发病机制密切相关。我们试图通过重组腺相关病毒介导的基因转移,在体内表达a β降解酶neprilysin。Neprilysin通过神经元回路的传入投射轴突传递到突触前部位。这种基因转移消除了neprilysin缺陷小鼠海马结构中Aβ水平的增加,也减少了突变淀粉样前体蛋白(APP)转基因小鼠的增加。在后一种情况下,由于从同侧运来的neprilysin,载体注射侧对侧海马形成中的a β水平也显著降低。此外,衰老突变型APP转基因小鼠的淀粉样蛋白沉积明显减慢。这些结果表明,neprilysin的突触前定位有助于有效和广泛地清除a β,并保护突触免受a β的突触毒性,并且嘴唇调节neprilysin活性将是治疗和预防AD的一种有希望的策略。此外,这些结果表明,直接将a β降解剂引入大脑的基因疗法可能具有治疗AD的潜力。少
项目成果
期刊论文数量(79)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Wang et al.: "Oxidized neprilysin in aging and Alzheimer's disease brains."Biochem.Biophys.Res.Commun.. 310. 238-243 (2003)
Wang 等人:“衰老和阿尔茨海默病大脑中的氧化脑啡肽酶。”Biochem.Biophys.Res.Commun.. 310. 238-243 (2003)
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- 影响因子:0
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Twata N., Saido TC.: "Mapping the progress of Alzheimer's and Parkinson's Disease. (Mizuno Y., Fisher A., and Haninr, I. eds.)"Kluwer Academic/Plenum Publishers, New York. 565 (2002)
Twata N.、Saido TC.:“绘制阿尔茨海默病和帕金森病的进展图。(Mizuno Y.、Fisher A. 和 Haninr, I. 编辑)”Kluwer Academy/Plenum Publishers,纽约。
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岩田修永: "アルツハイマー病の基礎と臨床、2.成因に関する分子生物学的アプローチ"Geriatric Med.. 40(9). 1302-1304 (2002)
Nounaga Iwata:“阿尔茨海默氏病的基础和临床方面,2. 发病机制的分子生物学方法”Geriatric Med.. 40(9) (2002)。
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Iwata et al.: "Region-specific Reduction of Aβ-degrading Endopeptidase, Neprilysin, in Mouse Hippocampus upon Aging."J.Neurosci.Res.. 70(3). 493-500 (2002)
Iwata 等人:“衰老时小鼠海马中 Aβ 降解内肽酶、脑啡肽酶的区域特异性减少。”J.Neurosci.Res. 70(3) (2002)。
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Masanori Tomioka, Keiro Shirotani, Nobuhisa Iwata, Han-Jun Lee, Fusheng Yang, Greg M. Cole, Yousuke Seyama, Takaomi C.Saido.: "In Vivo Role of Caspases in Excitotoxic Neuronal Death : Generation and Analysis of Transgenic Mice Expressing Baculoviral Caspa
Masanori Tomioka、Keiro Shirotani、Nobuhisa Iwata、Han-Jun Lee、Fusheng Yang、Greg M. Cole、Yousuke Seyama、Takaomi C.Saido.:“Caspases 在兴奋性毒性神经元死亡中的体内作用:表达杆状病毒的转基因小鼠的生成和分析
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IWATA Nobuhisa其他文献
IWATA Nobuhisa的其他文献
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{{ truncateString('IWATA Nobuhisa', 18)}}的其他基金
Pathophysiological roles of convulsive neurological disease-causing gene PRRT2 in the synapse
惊厥神经疾病致病基因 PRRT2 在突触中的病理生理作用
- 批准号:
18H02720 - 财政年份:2018
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Identification and functional analysis of brain catechin-binding proteins using aliphatic catechin derivatives
使用脂肪族儿茶素衍生物鉴定脑儿茶素结合蛋白并进行功能分析
- 批准号:
15K14971 - 财政年份:2015
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Identification and functional analysis of endogenous factors modulating a cutout of Abeta from APP
APP 中调节 Abeta 剪切的内源因子的鉴定和功能分析
- 批准号:
25293019 - 财政年份:2013
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Identification and functional analysis of gamma-secretase-modulating factors
γ-分泌酶调节因子的鉴定和功能分析
- 批准号:
24659034 - 财政年份:2012
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Analysis of functional roles of Ca^<2+>-dependent protease calpain in neuronal cell death
Ca^2依赖性蛋白酶钙蛋白酶在神经元细胞死亡中的功能作用分析
- 批准号:
17390026 - 财政年份:2005
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Identification of the major in vivo ABl-42-degrading catabolic-system in brain parenchyma.
脑实质中主要的体内ABl-42降解分解代谢系统的鉴定。
- 批准号:
12672167 - 财政年份:2000
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
相似海外基金
The analysis of the transportation of amyloid-β peptide across the blood-brain barrier
β淀粉样肽跨血脑屏障转运分析
- 批准号:
21790841 - 财政年份:2009
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Study of generation of Alzheimer's amyloid β peptide
阿尔茨海默病β淀粉样蛋白肽生成的研究
- 批准号:
13680814 - 财政年份:2001
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)