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: 10602413
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602413
• 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; 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; Genes; Goals; Golgi Apparatus; Grant; Guanosine Triphosphate Phosphohydrolases; Impairment; Length; Measures; Melatonin; Methods; Mitochondria; Morphology; Motor; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; 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; Study models; Synapses; Therapeutic; Toxic effect; Transfection; Transmission Electron Microscopy; Wild Type Mouse; blood-brain barrier crossing; brain tissue; experimental study; inhibitor; mitochondrial dysfunction; mouse model; mutant; neuroprotection; pre-clinical; preclinical study; prevent; protective effect; receptor; small molecule; success; tau Proteins; 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 (mt) 靶向小分子 SS31 和 mt 分裂抑制剂 1 (Mdivi-1) 对阿尔茨海默病 (AD) 小鼠的有益作用 模型。多项证据表明，年龄和淀粉样蛋白 β (Aβ) 诱导的活性氧 (ROS) 与 AD 中的 mt 和突触损伤有关。多项研究，包括初步研究 拟议的研究在很大程度上是基于该研究发现，在死后 AD 大脑标本和大脑中 AD 小鼠组织中，Aβ 与 mt 以及 ROS 产生水平增加和 mt 功能障碍相关， 提示Aβ可能是mt功能障碍和神经元损伤的关键因素。根据这些观察， 靶向 mt ROS 可能是减缓 AD 进展的重要治疗方法。然而，临床 对 AD 患者进行试验，以确定基于天然抗氧化剂的药物（天然抗氧化剂、 包括 VitC、VitE、β-胡萝卜素和褪黑激素）来减缓疾病进展，但效果有限。那 研究确实揭示了重要信息：天然抗氧化剂无法穿过血脑 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，开发了 mt 靶向分子 SS31，并已 在神经退行性疾病小鼠模型中已被证明可以穿过血脑屏障。然而，其 尚未在 AD 小鼠模型中进行临床前研究，也未在 AD 患者中进行临床研究。进一步地，在 其他有关 AD 疾病进展、mt 动力学缺陷（裂变增加和融合减少）的研究 发现于 AD 神经元中。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 tau 相互作用，导致 mt 过度断裂，ROS 产生增加， mt 到突触的运输有缺陷、突触 ATP 低和突触功能障碍。初步高通量 研究发现，mt 分裂抑制剂 Mdivi1 可减少 mt 过度分裂并增加 mt 融合 AD 细胞模型，表明 Mdivi1 是治疗 AD 的有前途的药物。我们 R01 应用程序的目标 目的是确定 APP-KI 中 SS31（目标 1）、Mdivi-1（目标 2）和 SS31+Mdivi1（目标 3）的保护作用，以及 AD 和非转基因 WT 小鼠的 tau-Tg 小鼠模型，处于疾病的两个阶段（预防和治疗） 进展。使用最先进的方法、mt 结构和功能变化、Aβ 和 tau 病理学，以及 将在 SS31、Mdivi1、SS31+Mdivi1 处理和未处理的 APP-KI 和 tau-Tg 中研究突触改变 小鼠和非转基因WT小鼠。拟议研究的结果将使研究人员更接近 开发能够减缓 AD 进展并最终治愈 AD 的治疗方法。