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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：
10516773
负责人：
Eugenia Trushina
金额：
$ 227.19万
依托单位：
MAYO CLINIC ROCHESTER
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 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10516773
关键词：
3-Dimensional Abeta synthesis Affinity Age of Onset Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Animal Model Astrocytes Binding Binding Sites Biochemistry Bioenergetics Biological Biological Assay Biological Markers Brain Cells Cellular biology Chemical Structure Chlorides Chronic Clinical Trials Coculture Techniques Complex Cryoelectron Microscopy Data Databases Dendritic Spines Development Disease Elements Ensure Epigenetic Process Failure Female Flavin Mononucleotide Future Genetic Goals Grant Homeostasis Human Immune response Immune system Impaired cognition In Vitro Inflammation Knock-in Mouse Late Onset Alzheimer Disease Legal patent Libraries Long-Term Potentiation Longevity Magnetic Resonance Imaging Medicine Metabolic Metformin Microglia Mitochondria Modification Molecular Monitor Multiomic Data Mus Nerve Degeneration Neurons Oxidative Stress Pathway interactions Patients Pharmacology Phenotype Play Production Reactive Oxygen Species Reporter Resistance Role Rotenone Safety Sex Differences Sheep Signal Transduction Site Specificity Stress Structure Structure-Activity Relationship Synapses Techniques Therapeutic Translations Treatment Efficacy Ubiquinone United States National Institutes of Health Validation X-Ray Crystallography abeta toxicity age related neurodegeneration apolipoprotein E-4 behavior measurement biological adaptation to stress blood-based biomarker brain cell cognitive function cognitive performance design diphenyliodonium drug candidate drug discovery druggable target effective therapy efficacious treatment efficacy validation experimental study familial Alzheimer disease fluorodeoxyglucose positron emission tomography healthspan healthy aging human disease human model improved in vivo induced pluripotent stem cell inhibitor innovation male metabolomics mouse model multiple omics neuroprotection neurotransmission novel novel lead compound novel therapeutic intervention pre-clinical prevent proteostasis small molecule synaptic function therapeutic target tool transcriptomics translational potential treatment effect treatment response

项目摘要

Alzheimer’s Disease (AD) has no effective treatments, and recent clinical trials focused on preventing of amy- loid beta (Aβ) production have consistently failed. Alternative approaches are urgently needed. We identified mitochondrial complex I (MCI) as a small molecule druggable target for AD. Partial inhibition of MCI induced multifaceted adaptive stress response activating neuroprotective mechanisms in multiple familial mouse mod- els of AD. Chronic treatment with MCI inhibitors was efficacious after the onset of cognitive dysfunction, reduc- ing inflammation, oxidative stress, Aβ and pTau, leading to improved synaptic function, brain energetics, and cognitive performance, ultimately blocking the ongoing neurodegeneration. Translational potential was sup- ported by cross-validation of the mouse data with the human transcriptomic data from the NIH AMP-AD data- base, demonstrating that pathways improved by the treatment in AD mice, including the immune system re- sponse and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients. While mounting data suggest that the induction of mild energetic stress via MCI inhibition could promote longevity, increase health span, and delay the onset of age-related neurodegenerative disease, including AD, the mecha- nistic understanding of what makes targeting of MCI with small molecules safe is lacking. It is also remains to be determined whether this treatment could be beneficial in patients with late onset AD (LOAD), the most prev- alent form of the disease. The objective of this competitive renewal is to conduct structure-activity relationship studies using isolated mam- malian MCI, and array of biochemistry and cell biology techniques, reporter cells and human neurons, and a library of novel and established MCI inhibitors to determine what factors, including the site of MCI inhibition, binding affinity, levels and sites of ROS production, and the structure of small molecules ensure safety of MCI inhibition and the induction of a neuroprotective signaling. We will next validate efficacy of novel MCI inhibitor developed and patented in the lab in 3D co-cultures of neurons/astrocytes/microglia derived from the iPSCs of LOAD male and female patients. Finally, therapeutic efficacy and molecular mechanisms will be confirmed in APOE4 Knock In mouse model of LOAD. Cross-validation of multi-omics data with the existing human metabolic, epigenetic and transcriptomic databases will determine specific mechanisms reversed by the treatment in male and female LOAD patients, supporting translational value of this innovative therapeutic approach. Novel infor- mation delineating MCI as a small molecule druggable therapeutic target generated using isolated mammalian MCI, and advanced techniques, including cryo-EM, could significantly advance the field of drug discovery for AD and other diseases. Mechanistic studies using human and animal models of LOAD could provide novel evidence for the cell-specific role mitochondrial adaptive stress response plays in neuroprotection. Translational bi- omarkers of therapeutic efficacy could aid in the design of future clinical trials.

阿尔茨海默氏病（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氏病，类β蛋白（Aβ）的生产一直失败。迫切需要采取替代办法。我们确定线粒体复合物I（MCI）作为AD的小分子药物靶点。MCI诱导的部分抑制多个家族性小鼠模型的多方面适应性应激反应激活神经保护机制的AD。MCI抑制剂的长期治疗在认知功能障碍发作后有效，抑制炎症、氧化应激、Aβ和pTau，从而改善突触功能、大脑能量学和认知能力，最终阻止正在进行的神经退化。翻译潜力很大- 通过小鼠数据与来自NIH AMP-AD数据的人类转录组数据的交叉验证移植- 基地，证明了AD小鼠的治疗改善了途径，包括免疫系统的重建，自发和神经传递，代表了AD患者治疗功效的基本机制。而越来越多的数据表明，通过MCI抑制诱导轻度能量应激可以促进长寿，增加健康寿命，并延迟年龄相关的神经退行性疾病的发作，包括AD，缺乏对是什么使得用小分子靶向MCI安全的科学理解。它也仍然是确定这种治疗是否对迟发性AD（LOAD）患者有益，这是一种罕见的疾病。本竞争性更新的目的是使用分离的mam进行构效关系研究，马里MCI，以及生物化学和细胞生物学技术阵列，报告细胞和人类神经元，以及新的和已建立的MCI抑制剂库，以确定哪些因素，包括MCI抑制的位点，结合亲和力、ROS产生的水平和位点以及小分子的结构确保MCI的安全性抑制和诱导神经保护信号传导。接下来，我们将验证新型MCI抑制剂的功效。在实验室中开发并获得专利的神经元/星形胶质细胞/小胶质细胞的3D共培养物，装载男性和女性患者。最后，治疗效果和分子机制将在在LOAD小鼠模型中的APOE 4敲除。多组学数据与现有的人类代谢，表观遗传学和转录组学数据库将确定在男性中通过治疗逆转的具体机制。和女性LOAD患者，支持这种创新治疗方法的转化价值。新闻资讯使用分离的哺乳动物产生的描述MCI作为小分子可药物治疗靶点的信息 MCI和先进的技术，包括冷冻EM，可以显着推进AD药物发现领域和其它疾病。使用LOAD的人类和动物模型的机制研究可以提供新的证据线粒体适应性应激反应在神经保护中的细胞特异性作用。翻译双- 治疗效果的标志物可以帮助设计未来的临床试验。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease.

DOI：
10.3233/jad-161088
发表时间：
2017
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
0
作者：
Tönnies E;Trushina E
通讯作者：
Trushina E

Cisplatin induces mitochondrial deficits in Drosophila larval segmental nerve.

DOI：
10.1016/j.nbd.2016.10.003
发表时间：
2017-01
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
Podratz, Jewel L.;Lee, Han;Knorr, Patrizia;Koehler, Stephanie;Forsythe, Steven;Lambrecht, Kelsey;Arias, Suzette;Schmidt, Kiley;Steinhoff, Gabrielle;Yudintsev, Georgiy;Yang, Amy;Trushina, Eugenia;Windebank, Anthony
通讯作者：
Windebank, Anthony

Application of Metabolomics in Alzheimer's Disease.

DOI：
10.3389/fneur.2017.00719
发表时间：
2017
期刊：
Frontiers in neurology
影响因子：
3.4
作者：
Wilkins JM;Trushina E
通讯作者：
Trushina E

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane.

DOI：
10.1016/j.nbd.2018.02.003
发表时间：
2018-06
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Zhang L;Trushin S;Christensen TA;Tripathi U;Hong C;Geroux RE;Howell KG;Poduslo JF;Trushina E
通讯作者：
Trushina E

Corrigendum to "Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's disease" [EBioMedicine 2 (2015) 294-305].

“调节线粒体复合物 I 活性可避免家族性阿尔茨海默病多种动物模型中的认知能力下降”的勘误表 [EBioMedicine 2 (2015) 294-305]。

DOI：
10.1016/j.ebiom.2019.03.062
发表时间：
2019
期刊：
EBioMedicine
影响因子：
11.1
作者：
Zhang,Liang;Zhang,Song;Maezawa,Izumi;Trushin,Sergey;Minhas,Paras;Pinto,Matthew;Jin,Lee-Way;Prasain,Keshar;Nguyen,ThiDT;Yamazaki,Yu;Kanekiyo,Takahisa;Bu,Guojun;Gateno,Benjamin;Chang,Kyeong-Ok;Nath,KarlA;Nemutlu,Emirhan;Dz
通讯作者：
Dz