Mitochondrial dysfunction and tau pathology in Alzheimer's disease
阿尔茨海默病中的线粒体功能障碍和 tau 病理学
基本信息
- 批准号:10805120
- 负责人:
- 金额:$ 42.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-16 至 2025-09-15
- 项目状态:未结题
- 来源:
- 关键词:3-Dimensional3xTg-AD mouseAddressAdultAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAnimalsAttenuatedBilateralBioenergeticsBiological ModelsBiologyBrainCellsComplexDataData SetDementiaDevelopmentDiseaseDisease ProgressionElectron TransportEtiologyEventEvolutionExhibitsFutureGenesHarvestHippocampusHypoxiaImpairmentInjectionsInterventionInvestigationLightLinkMeasuresMetabolicMetabolismMitochondriaModelingModificationMorphologyMusNeuronal DysfunctionNeuronsNucleic AcidsOxidative PhosphorylationOxidative StressPathogenesisPathologicPathologyPhotosensitizing AgentsProductionProteinsProton PumpProton-Motive ForceProtonsReactive Oxygen SpeciesResearchRoleSliceStudy modelsSymptomsSystemTauopathiesTechnologyTestingTherapeuticTimeToxinabeta oligomerexperimental studyin vivoin vivo Modelinnovationinsightmacromoleculemitochondrial dysfunctionmouse modelneonatal brainnew technologynoveloptogeneticsoxidationoxidized lipidpreservationpreventresponsespatiotemporalstress granuletau Proteinstau aggregationtau-1therapeutic developmenttoolwirelesswireless implant
项目摘要
Alzheimer’s disease (AD) is the most common cause of dementia with no current interventions that halt or
substantially slow disease progression. AD is a multifactorial disease characterized by impaired mitochondrial
bioenergetics, oxidative stress, and tau pathology. These AD pathologies are interconnected, change over time,
and correlate with neuronal dysfunction. Moreover, the hallmarks are dynamic and difficult to isolate
experimentally, which makes assigning causation challenging and limits therapeutic development. This proposal
uses novel optogenetic technology developed for hypoxic biology to address this gap and test if mitochondrial
dysfunction and reactive oxygen species (ROS) production are causal for the progression of tau pathology. Our
approach involves directly controlling mitochondrial function and ROS production using light, without interfering
with metabolism or using irreversible toxins with off-target effects. The optogenetic tools mitochondria-ON
(mtON) and mitochondria-OFF (mtOFF) are mitochondria-targeted light-activated proton pumps that alter
mitochondrial bioenergetics to turn ‘on’ or ‘off’ mitochondrial function in response to light. Similarly, mtSuperNova
is a mitochondria-targeted genetically-encoded photosensitizer which generates ROS in response to light. These
tools will spatiotemporally control mitochondrial function and ROS production in both an ex vivo brain slice culture
and an in vivo mouse model using the PS19 mouse line (P301S tau). These mice exhibit early mitochondrial
dysfunction and have been used extensively to study tau pathology and are an optimal model for these studies.
Organotypic brain slice cultures will be used to provide a three-dimensional system to mechanistically test when
and how mitochondrial energetics and ROS production contribute to pathological tau modifications. AD is largely
associated with aging; therefore, in we will bridge our ex vivo findings into an adult in vivo model. Using a wireless
optogenetic system, we will illuminate hippocampi in live, freely moving PS19 adult mice to test the effect of
mitochondrial dysfunction over time on measures of oxidative stress and tau pathology. Mitochondrial
dysfunction and ROS production have long been associated with AD pathology however the cause-and-effect
relationship is unclear. Our novel technology provides an approach to directly test the role of mitochondria in AD
independent of confounding factors. Overall, these studies will begin to clearly define the role of mitochondria in
the evolution of tau pathology and provide mechanistic insights into therapeutic opportunities to attenuate AD
pathogenesis.
阿尔茨海默病(AD)是痴呆症的最常见原因,目前没有停止或
大大减缓疾病进展。AD是一种多因素疾病,其特征在于线粒体受损
生物能量学、氧化应激和tau病理学。这些AD病理是相互关联的,随着时间的推移而变化,
并与神经元功能障碍有关。此外,这些特征是动态的,很难孤立出来
实验上,这使得分配因果关系具有挑战性,并限制了治疗的发展。这项建议
使用为缺氧生物学开发的新型光遗传学技术来解决这一差距,并测试线粒体
功能障碍和活性氧(ROS)产生是tau病理学进展的原因。我们
这种方法涉及使用光直接控制线粒体功能和ROS产生,而不干扰
或使用具有脱靶效应的不可逆毒素。光遗传学工具ESPA-ON
(mtON)和线粒体关闭(mtOFF)是靶向线粒体的光激活质子泵,
线粒体生物能量学以响应于光而“打开”或“关闭”线粒体功能。同样,mtSuperNova
是一种靶向的基因编码光敏剂,对光有反应时产生ROS。这些
这些工具将在离体脑切片培养物中时空控制线粒体功能和ROS产生,
以及使用PS19小鼠系(P301 S tau)的体内小鼠模型。这些小鼠表现出早期线粒体
功能障碍,并已广泛用于研究tau病理学,是这些研究的最佳模型。
器官型脑切片培养将用于提供三维系统,以机械地测试何时
以及线粒体能量学和ROS产生如何促进病理性tau蛋白修饰。AD主要是
与衰老相关;因此,我们将把我们的离体研究结果与成人体内模型联系起来。使用无线
光遗传学系统,我们将在活的、自由移动的PS19成年小鼠中照射光营,以测试光遗传学系统的作用。
随着时间的推移,线粒体功能障碍对氧化应激和tau病理学的测量。线粒体
长期以来,功能障碍和ROS产生与AD病理学有关,
关系不清楚。我们的新技术提供了一种直接测试线粒体在AD中作用的方法
独立于混杂因素。总的来说,这些研究将开始明确定义线粒体在
tau病理学的演变,并提供对减轻AD的治疗机会的机制见解
发病机制
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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Gail V. W. Johnson其他文献
Glycogen Synthase Kinase 3β Phosphorylates Tau at Both Primed and Unprimed Sites
糖原合酶激酶 3β 在引发和未引发的位点磷酸化 Tau
- DOI:
- 发表时间:
2003 - 期刊:
- 影响因子:4.8
- 作者:
Jae;Gail V. W. Johnson - 通讯作者:
Gail V. W. Johnson
Metal-catalyzed oxidation of bovine neurofilaments in vitro.
牛神经丝的体外金属催化氧化。
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:7.4
- 作者:
Juan C. Troncoso;Anthony C. Costello;James H. Kim;Gail V. W. Johnson - 通讯作者:
Gail V. W. Johnson
Gail V. W. Johnson的其他文献
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{{ truncateString('Gail V. W. Johnson', 18)}}的其他基金
Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte
星形胶质细胞中转谷氨酰胺酶 2 (TG2) 介导的基因表达机制
- 批准号:
10293984 - 财政年份:2021
- 资助金额:
$ 42.35万 - 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
- 批准号:
10269305 - 财政年份:2021
- 资助金额:
$ 42.35万 - 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
- 批准号:
10461933 - 财政年份:2021
- 资助金额:
$ 42.35万 - 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
- 批准号:
10667539 - 财政年份:2021
- 资助金额:
$ 42.35万 - 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
- 批准号:
10374933 - 财政年份:2020
- 资助金额:
$ 42.35万 - 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
- 批准号:
10188394 - 财政年份:2020
- 资助金额:
$ 42.35万 - 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
- 批准号:
10601125 - 财政年份:2020
- 资助金额:
$ 42.35万 - 项目类别:
Tau protein turnover and mitochondrial stress responses
Tau 蛋白周转和线粒体应激反应
- 批准号:
9761421 - 财政年份:2018
- 资助金额:
$ 42.35万 - 项目类别:
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