Mitochondrial Molecules as Therapeutic Drugs for Alzheimer's Disease

线粒体分子作为阿尔茨海默病的治疗药物

• 批准号: 10223188
• 负责人: P. Hemachandra Reddy
• 金额: $ 65.11万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223188
• 关键词: Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Antioxidants; Applications Grants; Area; Autopsy; Behavior; Beta Carotene; Biology; Blood - brain barrier anatomy; Brain; Cardiolipins; Cell Culture Techniques; Cell Survival; Cell model; Cells; Clinical; Clinical Trials; Cognitive; Combined Modality Therapy; Complementary DNA; Complex; Data; Defect; Dendritic Spines; Disease Progression; Drug Kinetics; Electron Transport; Equilibrium; Functional disorder; Funding; Gene Expression; Goals; Golgi Apparatus; Grant; Guanosine Triphosphate Phosphohydrolases; Impairment; Knock-in Mouse; Length; Measures; Melatonin; Methods; Mitochondria; Morphology; Motor; Mus; Neurodegenerative Disorders; Neurons; Outcome; Oxidative Stress; Pathogenesis; Pathology; Pharmaceutical Preparations; Preventive; Production; Proteins; Reactive Oxygen Species; Reporting; Research; Research Personnel; Respiration; Rodent Model; Senile Plaques; Specimen; Stains; Structure; Study models; Synapses; Therapeutic; Toxic effect; Transmission Electron Microscopy; Wild Type Mouse; base; blood-brain barrier crossing; brain tissue; experimental study; inhibitor/antagonist; mitochondrial dysfunction; mouse model; mutant; pre-clinical; preclinical study; prevent; protective effect; receptor; small molecule; success; tau Proteins; tau aggregation; tau-1; therapeutic development

The objective of this application is to better understand the beneficial effects of the mitochondria (mt)-targeted small molecule SS31 and the mt division inhibitor 1 (Mdivi-1) in Alzheimer’s disease (AD) mouse models. Several lines of evidence suggest that age- and amyloid beta (Aβ)-induced reactive oxygen species (ROS) is associated with mt and synaptic damage in AD. Several studies, including preliminary studies on which the proposed research is in large part based, found that, in postmortem AD brain specimens and brain tissues from AD mice, Aβ is associated with mt and increased levels of ROS production and mt dysfunction, suggesting that Aβ may be a key factor in mt dysfunction and neuronal damage. Based on these observations, targeting mt ROS may be an important therapeutic approach to slowing AD progression. However, clinical trials of AD patients to determine the capability of natural antioxidant-based drugs (natural antioxidants, including VitC, VitE, beta-carotene, and melatonin) to slow disease progression yielded limited success. That research did reveal critical information: that natural antioxidants are not capable of crossing the blood brain barrier and are not capable of reaching critical brain areas affected by AD and so cannot protect mt and synapses in those areas. To overcome this challenge, mt-targeted molecule SS31 was developed and has been proven to cross the blood brain barrier in mouse models of neurodegenerative diseases. However, its efficacies have not been studied preclinically in AD mouse models and clinically in AD patients. Further, in other studies of AD disease progression, defective mt dynamics (increased fission and decreased fusion) were found in AD neurons. Results from others and our preliminary studies revealed that the fission protein Drp1 interacts with Aβ and phosphorylated tau, resulting in excessive mt fragmentation, increased ROS production, defective transport of mt to synapses, low synaptic ATP, and synaptic dysfunction. Preliminary high throughput studies found that mt division inhibitor Mdivi1 reduces excessive mt fragmentation and increases mt fusion in cell models of AD, suggesting that Mdivi1 is a promising drug to treat AD. The objective of our R01 application is to determine protective effects of SS31 (Aim 1), Mdivi-1 (Aim 2), and SS31+Mdivi1 (Aim 3) in APP-KI and tau-Tg mouse models of AD and non-transgenic WT mice, at 2 stages (preventive and curative) of disease progression. Using state-of-the-art methods, mt structural and functional changes, Aβ and tau pathologies, and synaptic alterations will be studied in SS31-, Mdivi1-, SS31+Mdivi1-treated and untreated APP-KI and tau-Tg mice and non-transgenic WT mice. The outcome of the proposed research will take researchers closer to developing therapeutic approaches capable of slowing AD progression – and, ultimately, of curing AD.

本应用的目的是更好地了解线粒体靶向小分子SS31和线粒体分裂抑制物1(Mdivi-1)对阿尔茨海默病(AD)小鼠的有益效果 模特们。几条证据表明，年龄和淀粉样β蛋白(Aβ)诱导的活性氧物种 (ROS)与阿尔茨海默病的MT和突触损伤有关。几项研究，包括关于 这项拟议的研究在很大程度上是基于，发现在死后AD的大脑样本和大脑中 来自AD小鼠的组织中，Aβ与线粒体、ROS产生水平的增加和线粒体功能障碍有关， 提示A-β可能是MT功能障碍和神经元损伤的关键因素。基于这些观察， 靶向mt ROS可能是减缓AD进展的重要治疗方法。然而，临床上 AD患者的试验以确定天然抗氧化剂为主的药物(天然抗氧化剂， 包括维生素C、维生素E、β-胡萝卜素和褪黑素)来减缓疾病进展，但收效甚微。那 研究确实揭示了关键信息：天然抗氧化剂不能穿过血脑 屏障，无法到达受AD影响的关键大脑区域，因此无法保护mt和 这些区域的突触。为了克服这一挑战，mt靶向分子SS31被开发出来并已经 在神经退行性疾病的小鼠模型中已被证明可以穿越血脑屏障。然而，它的 其有效性尚未在AD小鼠模型和AD患者中进行临床前研究。此外，在 其他关于AD疾病进展、mt动力学缺陷(分裂增加和融合减少)的研究是 在阿尔茨海默病神经元中发现。其他人和我们的初步研究结果表明，裂变蛋白Drp1 与Aβ和磷酸化的tau相互作用，导致线粒体过度碎裂，增加ROS产生， 线粒体到突触的运输缺陷，突触三磷酸腺苷水平低下，以及突触功能障碍。初步的高吞吐量 研究发现，MT分裂抑制剂MDi1减少了MT过度碎裂并增加了MT融合 阿尔茨海默病的细胞模型，提示MDi1是一种有前途的治疗AD的药物。我们R01应用程序的目标是 目的是确定SS31(目标1)、Mdivi-1(目标2)和SS31+MDi1(目标3)在APP-KI中的保护作用 处于疾病预防和治愈两个阶段的tau-tg小鼠AD模型和非转基因WT小鼠 进步。使用最先进的方法，mt结构和功能变化，Aβ和tau病理，以及 将研究SS31-、MDi1-、SS31+MDi1处理和未处理的APP-KI和tau-TG的突触变化 小鼠和非转基因WT小鼠。拟议中的研究结果将使研究人员更接近 开发能够减缓AD进展的治疗方法--并最终治愈AD。