BRAIN PROTEIN OXIDATION IN AD, MCI, AND PCAD: ROLES OF AB AND PIN1

AD、MCI 和 PCAD 中的脑蛋白氧化：AB 和 PIN1 的作用

• 批准号: 8050035
• 负责人: D. Allan Butterfield
• 金额: $ 38.74万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8050035
• 关键词: Abeta synthesis; Accounting; Affect; Affinity; Age-Months; Alanine; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; Binding; Binding Sites; Biological Assay; Brain; Brain region; Caenorhabditis elegans; Cerebellum; Cerebral cortex; Cessation of life; Codon Nucleotides; Collaborations; Cysteine; Data; Dementia; Dependovirus; Depressed mood; Digestion; Disease; Electrospray Ionization; Ensure; Environment; Event; Free Radicals; Functional disorder; Human; Hydrophobicity; In Vitro; Individual; Institutes; Isomerase; Knock-in Mouse; Laboratories; Lead; Length; Leucine; Lipid Peroxidation; Measures; Mediating; Mediator of activation protein; Methionine; Methodology; Methods; Microtubules; Modeling; Modification; Mus; Mutate; N-terminal; NADPH Oxidase; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Norleucine; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathology; Peptides; Peptidylprolyl Isomerase; Persons; Play; Positioning Attribute; Process; Progress Reports; Proline; Property; Protein Binding; Protein Biosynthesis; Protein Dephosphorylation; Proteins; Proteomics; RNA; Recombinants; Research; Research Personnel; Role; Senile Plaques; Series; Serine; Side; Site; Small Interfering RNA; Solubility; Source; Specificity; Staging; Tauopathies; Testing; Therapeutic Intervention; Threonine; Time; Transgenic Mice; Transgenic Organisms; Triose-Phosphate Isomerase; Western Blotting; Wild Type Mouse; abeta deposition; abeta toxicity; aging brain; base; disorder control; genetic regulatory protein; human DNA; in vivo; in vivo Model; indexing; insight; knock-down; mild neurocognitive impairment; mind control; mutant; nervous system disorder; neurotoxic; neurotoxicity; novel; numb protein; oxidation; oxidative damage; pre-clinical; protein aminoacid sequence; success; tandem mass spectrometry; tau Proteins; tau phosphorylation; therapeutic target

Oxidative stress is present in Alzheimer's disease (AD) brain, and we recently provided evidence that protein oxidation and lipid peroxidation are also present in brains of persons with mild cognitive impairment (MCI). Our lab first used redox proteomics to identify oxidatively modified proteins in AD and MCI brain. One protein that is oxidatively modified and dysfunctional in both AD and MCI is Pin1, a regulatory protein of many functions relevant to neurodegeneration. One source of oxidative stress in AD is amyloid beta-peptide (AP). The single methionine (Met) of Ap appears to be critical to the oxidative stress induced by Ap. Our overall hypothesis is A(3-mediated oxidative modification of brain Pin1 is fundamental to the progression of AD and occurs via mechanisms involving the single Met of AfJ. To test this overall hypothesis, a series of Specific Aims are proposed. In Specific Aim 1, oxidative stress indices and redox proteomics of preclinical AD (PCAD) brain will be undertaken to test the hypothesis that Pin 1 is oxidatively modified and must be important in the progression of AD. In Specific Aim 2, to determine the temporal role of toxic aggregated AP in the in vivo oxidative modification of Pin 1, we will use redox proteomics to test the hypothesis that in human mutant APP/PS-1 knock in mice oxidative modification and dysfunction of Pin1 will occur. In Specific Aim 3, we will test the hypothesis that Pin 1 in neuronal cultures will be oxidatively dysfunctional by aggregated toxic forms of Ap. In Specific Aim 4, we will test the hypothesis that in vivo elevation of Pin 1 will result in decreased levels of phospho-tau and Ap in brain of APP/PS-1 mice. In Specific Aim 5, we will test the hypothesis that mechanisms involving the single Met residue of Ap are paramount in the in vivo toxic properties of Ap, including the oxidative modification of Pin1. In each Aim, correlation of the status of Ap (type, solubility, oligomerization, etc. determined by Core B) will be made. This proposal reflects a set of comprehensive and integrated studies that utilizes a variety of novel methodologies and that takes advantage of our expertise in oxidative stress, Ap, and redox proteomics applied to AD. Dr. K.P. Lu (Harvard), an acknowledged leader in Pin 1 research, will serve as a Senior Investigator and provide additional expertise. New insights into the oxidative stress, neurodegeneration and progression of AD are envisaged, as are insights into a potential treatment to slow or disrupt progression of MCI to AD.

氧化应激存在于阿尔茨海默病 (AD) 大脑中，我们最近提供的证据表明蛋白质 轻度认知障碍（MCI）患者的大脑中也存在氧化和脂质过氧化。 我们的实验室首先使用氧化还原蛋白质组学来识别 AD 和 MCI 大脑中的氧化修饰蛋白质。一 Pin1 是 AD 和 MCI 中被氧化修饰且功能失调的蛋白质，它是一种调节蛋白 许多与神经退行性变相关的功能。 AD 中氧化应激的来源之一是淀粉样β-肽 （美联社）。 Ap 的单一蛋氨酸 (Met) 似乎对于 Ap 诱导的氧化应激至关重要。我们的 总体假设是 A(3 介导的大脑 Pin1 氧化修饰是 AD 是通过涉及 AfJ 的单个 Met 的机制发生的。为了检验这一总体假设，进行了一系列 提出了具体目标。具体目标1，临床前的氧化应激指数和氧化还原蛋白质组学 AD (PCAD) 大脑将被用来测试 Pin 1 被氧化修饰并且必须被氧化的假设 AD 的进展中发挥着重要作用。在具体目标 2 中，确定有毒聚集 AP 的时间作用 在Pin 1的体内氧化修饰中，我们将使用氧化还原蛋白质组学来检验以下假设： 人类突变体APP/PS-1敲入小鼠体内会发生氧化修饰和Pin1功能障碍。具体来说 目标 3，我们将测试以下假设：神经元培养物中的 Pin 1 将出现氧化功能障碍 Ap 的聚集毒性形式。在具体目标 4 中，我们将测试以下假设：Pin 1 的体内升高将 导致 APP/PS-1 小鼠脑中磷酸 tau 和 Ap 水平降低。在具体目标 5 中，我们将测试 涉及 Ap 的单个 Met 残基的机制在体内毒性中至关重要的假设 Ap 的特性，包括 Pin1 的氧化修饰。每个Aim中，Ap状态的相关性 (类型、溶解度、低聚化等由Core B决定)。该提案反映了一系列 综合性和综合性的研究，利用了各种新颖的方法，并且需要 利用我们在氧化应激、Ap 和氧化还原蛋白质组学方面的专业知识应用于 AD。陈国鹏博士鲁 （哈佛大学）是 Pin 1 研究领域公认的领导者，他将担任高级研究员并提供 额外的专业知识。关于氧化应激、神经变性和 AD 进展的新见解 设想的，以及对减缓或破坏 MCI 向 AD 进展的潜在治疗方法的见解。