Mitochondrial Molecules in Alzheimer's Disease and Other Tauopathies

阿尔茨海默病和其他 Tau蛋白病中的线粒体分子

基本信息

批准号：
10836888
负责人：
P. Hemachandra Reddy
金额：
$ 38.21万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
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/10836888
关键词：
Affect Age Age Months Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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 Tauopathies 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

项目摘要

Project Summary 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 (A)-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, A is associated with mt and increased levels of ROS production and mt dysfunction, suggesting that A 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 A 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, A 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.

项目摘要该应用的目的是更好地了解线粒体（MT）的有益作用 - 阿尔茨海默氏病（AD）小鼠的靶向小分子SS31和MT分裂抑制剂1（MDIVI-1）型号。几条证据表明，年龄和淀粉样蛋白β（A）诱导的活性氧（ROS）与AD中的MT和突触损伤有关。几项研究，包括有关的初步研究拟议的研究在很大程度上是基于拟议的，发现在尸体AD大脑标本和大脑中来自AD小鼠的组织，A与MT和ROS产生和MT功能障碍的水平增加有关，表明A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。但是，临床 AD患者的试验确定天然抗氧化剂药物的能力（天然抗氧化剂，包括VITC，VITE，β-胡萝卜素和褪黑激素以减慢疾病进展的成功率有限。那研究确实揭示了关键信息：天然抗氧化剂无法跨越血液障碍，无法到达受广告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，开发了以mt为目标的分子SS31并具有事实证明，他在神经退行性疾病的小鼠模型中越过血脑屏障。但是，它 efucicaies先前尚未在AD小鼠模型中和AD患者的临床上进行研究。此外，在 AD疾病进展，缺陷MT动力学（裂变增加和融合降低）的其他研究是在AD神经元中发现。他人的结果和我们的初步研究表明，裂变蛋白DRP1 与A和磷酸化的tau相互作用，导致过量的MT碎片化，增加了ROS的产生， MT到突触，低突触ATP和突触功能障碍的有缺陷。初步高通量研究发现，MT分裂抑制剂MDIVI1减少了过量的MT碎片化并增加了MT融合 AD的细胞模型，表明MDIVI1是治疗AD的有前途的药物。我们的R01应用程序的目的是为了确定SS31（AIM 1），MDIVI-1（AIM 2）和SS31+MDIVI1（AIM 3）的受保护作用疾病的2个阶段（预防和治愈），AD和非转基因WT小鼠的Tau-TG小鼠模型进展。使用最先进的方法，MT结构和功能变化，A和TAU病理以及突触改动将在SS31-，MDIVI1-，SS31+MDIVI1处理和未经处理的App-KI和Tau-TG中进行研究小鼠和非转基因WT小鼠。拟议研究的结果将使研究人员更接近开发能够减慢AD进展的治疗方法，并最终固化AD。