Mitochondrial Complex I as a Target for Neuroprotection in AD
线粒体复合物 I 作为 AD 神经保护的靶点
基本信息
- 批准号:9752105
- 负责人:
- 金额:$ 6.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAbeta synthesisAdverse effectsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloid beta-ProteinAnimal ModelBehaviorBindingBioenergeticsBiologicalBiological MarkersBiological ModelsBlood - brain barrier anatomyBrain-Derived Neurotrophic FactorCellsChronicClinicClinicalClinical TrialsCombined Modality TherapyComplexDementiaDevelopmentDiabetes MellitusDiseaseEvaluationFDA approvedFailureFemaleFlavin MononucleotideGeneticGlycogen Synthase KinasesGoalsHumanIn VitroIncidenceIndividualInflammationKnock-in MouseKnock-outKnockout MiceLinkLongevityMetabolicMetforminMitochondriaMolecularMonitorMusNeuronsOutcomeOxidation-ReductionOxidative StressPathway interactionsPatientsPharmaceutical PreparationsPharmacogenomicsPharmacologyPhenotypePopulationPre-Clinical ModelPresenile Alzheimer DementiaPreventionProductionProtein KinaseProteinsPyronesReactive Oxygen SpeciesReportingResistanceSafetyStressSynapsesTechniquesTestingTherapeuticTransgenic AnimalsTranslatingTranslationsValidationapolipoprotein E-4biological adaptation to stressblood-based biomarkerclinical developmentcognitive developmentcognitive functioncohortdesigneffective therapyexperimental studyfamilial Alzheimer diseasegenetic approachglycogen synthase kinase 3 betahuman diseasehuman modelin vivoindividual responseindividualized medicineinduced pluripotent stem cellinhibitor/antagonistlymphoblastoid cell linemalemouse modelneuroprotectionnovelnovel therapeutic interventionpre-clinicalpreventprotein expressionrestorationsmall moleculetargeted biomarkertau Proteinstau aggregationtraffickingtranscriptomicstranslational engagementtranslational studytreatment response
项目摘要
Alzheimer's Disease (AD) has no effective treatments, and recent clinical trials focused on prevention of amy-
loid beta (Ab) production have consistently failed. Alternative approaches are urgently needed. We demon-
strated that partial inhibition of mitochondrial complex I with small molecule CP2 induced neuroprotection in
multiple mouse models of familial AD. While inhibition of complex I activity has been linked to prolonged lon-
gevity, we were the first to show that this approach could be beneficial for AD. CP2 penetrates the blood brain
barrier, and accumulates in mitochondria where it competes with the flavin mononucleotide for binding to the
redox center of complex I. Partial inhibition of complex I activity induced beneficial cellular adaptation to oxida-
tive stress and enhancement of cellular energetics, which was associated with a significant delay in the devel-
opment of cognitive and behavior phenotypes when independent groups of AD mice were treated at pre- or
symptomatic stages of the disease. However, along with the benefits of treatment that included a reduction of
soluble and insoluble Ab and pTau, inhibition of glycogen synthase kinase 3b activity, restoration of axonal traf-
ficking and levels of brain-derived neurotrophic factor and synaptic proteins, CP2 induced activation of AMP
activated protein kinase (AMPK). Taken into consideration detrimental effects reported in relation to the AMPK
activation in humans, to achieve efficacious and safe therapeutic response using mitochondrial complex I in-
hibitors in the context of AD, it is imperative to understand the molecular mechanisms to avoid failure in trans-
lating our findings into clinical settings. The specific experimental goals are: 1) to test the central hypothesis
that activation of AMPK is not required for CP2-induced neuroprotection; 2) to determine the hierarchy of mo-
lecular mechanisms other than AMPK activation involved in neuroprotection; 3) to confirm these mechanisms
in mouse models of AD that express both human Aβ and Tau protein (3xTgAD) and ApoE4 knock in mice that
resemble sporadic AD; 4) to establish blood-based biomarkers for target engagement for translational studies;
5) to determine translational potential of this approach in human neuronal cells; and 6) to conduct phar-
macogenomics study using lymphoblastoid cell lines from diverse healthy population to establish safety mar-
gins and individualized response to treatment.
The proposed studies will provide a rigorous evaluation of molecular mechanisms essential for CP2 neuropro-
tection and will investigate the translational potential and safety of this approach for AD using targeted genetic
perturbations and advanced techniques in multiple mouse and human model systems. The outcomes will justi-
fy the development of combination therapy to mitigate potentially harmful side effects, and biomarkers to moni-
tor target engagement and safety. Since the majority of experiments will be conducted in parallel with metfor-
min, the only complex I inhibitor that is FDA approved to treat diabetes, the outcomes will also provide the criti-
cal biological evidence to establish the rationale and the preclinical criteria, to support further clinical develop-
ment of specific MCI inhibitors for AD treatment.
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阿尔茨海默病(AD)没有有效的治疗方法,最近的临床试验集中在预防阿尔茨海默病上。
类β(Ab)的生产一直失败。迫切需要采取替代办法。我们恶魔-
研究表明,用小分子CP 2部分抑制线粒体复合物I可诱导神经保护作用,
家族性AD的多种小鼠模型。虽然复合物I活性的抑制与延长的长时间的
gevity,我们是第一个证明这种方法可能对AD有益的人。CP 2穿透血脑
屏障,并在线粒体中积累,在那里它与黄素单核苷酸竞争结合到线粒体中。
络合物I的氧化还原中心部分抑制复合物I活性诱导细胞对氧化应激的有益适应
积极的压力和增强细胞能量,这是与显着延迟的发展,
当独立组的AD小鼠在治疗前或治疗后接受治疗时,
疾病的症状阶段。然而,沿着治疗的好处,包括减少
可溶性和不溶性Ab和pTau,糖原合成酶激酶3b活性的抑制,轴突运输的恢复,
脑源性神经营养因子和突触蛋白的水平,CP 2诱导AMP激活
活化蛋白激酶(AMPK)。考虑到报告的与AMPK相关的有害影响
在人类中激活,以实现有效和安全的治疗反应,使用线粒体复合物I在-
在AD的背景下,必须了解分子机制,以避免反式治疗失败。
将我们的发现应用于临床具体的实验目标是:1)检验中心假设
CP 2诱导的神经保护作用不需要激活AMPK; 2)确定mo-的层次结构
AMPK激活以外的其他神经保护机制; 3)证实这些机制
在表达人Aβ和Tau蛋白(3xTgAD)和ApoE 4敲除小鼠AD模型中,
类似于散发性AD; 4)建立基于血液的生物标志物,用于转化研究的靶向接合;
5)以确定该方法在人神经元细胞中的翻译潜力;和6)进行Phar-
macgenomics研究使用来自不同健康人群的淋巴母细胞样细胞系建立安全标志物
gins和个体化的治疗反应。
拟议的研究将提供一个严格的评估的分子机制至关重要的CP 2神经保护,
并将使用靶向遗传学方法研究这种方法治疗AD的翻译潜力和安全性。
在多个小鼠和人类模型系统中的扰动和先进技术。结果只会-
促进联合治疗的发展,以减轻潜在的有害副作用,并监测生物标志物,
以确保目标的安全由于大多数实验将与metfor并行进行,
min是FDA批准用于治疗糖尿病的唯一一种复合物I抑制剂,其结果也将提供关键的
校准生物学证据,以确定原理和临床前标准,支持进一步的临床开发-
用于AD治疗的特异性MCI抑制剂。
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项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Eugenia Trushina其他文献
Eugenia Trushina的其他文献
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{{ truncateString('Eugenia Trushina', 18)}}的其他基金
Small Molecule Mitochondria-Targeted Therapeutics for AD (Supplement)
小分子线粒体靶向治疗 AD(补充)
- 批准号:
10621603 - 财政年份:2022
- 资助金额:
$ 6.65万 - 项目类别:
Small Molecule Mitochondria-Targeted Therapeutics for AD
小分子线粒体靶向治疗 AD
- 批准号:
10576450 - 财政年份:2021
- 资助金额:
$ 6.65万 - 项目类别:
Small molecule mitochondria-targeted therapeutics for Huntingtons Disease
亨廷顿病的小分子线粒体靶向疗法
- 批准号:
9925848 - 财政年份:2018
- 资助金额:
$ 6.65万 - 项目类别:
Small molecule mitochondria-targeted therapeutics for Huntingtons Disease
亨廷顿病的小分子线粒体靶向疗法
- 批准号:
10160973 - 财政年份:2018
- 资助金额:
$ 6.65万 - 项目类别:
Mitochondrial Complex I as a Target for Neuroprotection in AD
线粒体复合物 I 作为 AD 神经保护的靶点
- 批准号:
10516773 - 财政年份:2017
- 资助金额:
$ 6.65万 - 项目类别:
Mitochondrial dynamics and metabolomic biomarkers in neurodegenerative disorders
神经退行性疾病中的线粒体动力学和代谢组生物标志物
- 批准号:
8691816 - 财政年份:2011
- 资助金额:
$ 6.65万 - 项目类别:
Mitochondrial dynamics and metabolomic biomarkers in neurodegenerative disorders
神经退行性疾病中的线粒体动力学和代谢组生物标志物
- 批准号:
8216043 - 财政年份:2011
- 资助金额:
$ 6.65万 - 项目类别:
Mitochondrial dynamics and metabolomic biomarkers in neurodegenerative disorders
神经退行性疾病中的线粒体动力学和代谢组生物标志物
- 批准号:
8917330 - 财政年份:2011
- 资助金额:
$ 6.65万 - 项目类别:
Mitochondrial dynamics and metabolomic biomarkers in neurodegenerative disorders
神经退行性疾病中的线粒体动力学和代谢组生物标志物
- 批准号:
8917662 - 财政年份:2011
- 资助金额:
$ 6.65万 - 项目类别:
Mitochondrial dynamics and metabolomic biomarkers in neurodegenerative disorders
神经退行性疾病中的线粒体动力学和代谢组生物标志物
- 批准号:
8485606 - 财政年份:2011
- 资助金额:
$ 6.65万 - 项目类别:
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