Evaluation of Monoamine Oxidase-A as a New Biomarker for Alzheimer's Disease

单胺氧化酶 A 作为阿尔茨海默病新生物标志物的评价

• 批准号: 10525579
• 负责人: Jogeshwar Mukherjee
• 金额: $ 43.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525579
• 关键词: Aldehydes; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Ammonia; Amyloid beta-Protein; Animals; Anterior; Antidepressive Agents; Applications Grants; Arizona; Attention; Autopsy; Autoradiography; Binding; Biogenic Amines; Biological Markers; Brain; Brain imaging; Brain region; Chemicals; Chronic; Clorgyline; Cognitive; Cytosol; Dementia; Diagnosis; Dioxygen; Disease; Dopamine; Drug Evaluation; Enzymes; Etiology; Evaluation; Exhibits; Feasibility Studies; Flavoproteins; Fluorine; Fluoxetine; Goals; Grant; Harmine; Health; Hippocampus (Brain); Human; Hydrogen Peroxide; Hyperactivity; Hypoxia; Image; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Interleukin-13; Interleukin-4; Label; Major Depressive Disorder; Measures; Mental Depression; Microglia; Mitochondria; Molecular; Monoamine Oxidase A; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurotransmitters; Norepinephrine; Outer Mitochondrial Membrane; Oxidative Stress; Patients; Peripheral; Play; Positron-Emission Tomography; Production; Protein Isoforms; Proteins; Radioisotopes; Reaction; Reactive Oxygen Species; Reporting; Research; Research Institute; Rodent; Role; Sampling; Senile Plaques; Serotonin; Slice; Stains; Temporal Lobe; Translations; Up-Regulation; X Chromosome; Yang; analog; base; brain tissue; clinical anxiety; disorder control; drug development; entorhinal cortex; genetic signature; human tissue; imaging agent; imaging approach; imaging biomarker; imaging modality; imaging study; inflammatory marker; inhibitor; inhibitor therapy; macrophage; monoamine; monocyte; paired helical filament; potential biomarker; protein degradation; radiotracer; response; tau Proteins; tau-1; therapeutic development; therapeutically effective; treatment planning

Evaluation of Monoamine Oxidase-A as a New Biomarker for Alzheimer's Disease Project Summary This application is in response to PAR-19-071, “Research on current topics in Alzheimer's disease and its related dementias (ADRD)”. Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ plaque aggregation and Tau protein paired helical filaments causing neurofibrillary tangles (NFT) in the brain. Noninvasive brain imaging methods and peripheral measures of phosphorylated Tau isoforms (pTau181 and pTau217) are becoming reliable markers for AD. In addition to these biomarkers, translocator protein (TSPO) as a marker for inflammation is also being pursued in efforts to gain a comprehensive understanding of disease etiology. Imaging methods play a key role in understanding NFT accumulation in AD beginning in the entorhinal cortex and hippocampus, spreading to the temporal cortex and subsequently to the neocortex. Monoamine oxidase A (MAO-A), a mitochondrial enzyme found in neurons, deaminates monoamine neurotransmitters. Upregulation of MAO-A can cause oxidative stress leading to neurodegeneration. Currently, no PET imaging studies have been reported on MAO-A in AD patients. [11C]Harmine, a MAO-A PET radiotracer has been used in human studies of depression, but no reports exist in AD. In autoradiographic studies using [18F]FEH (an analog of harmine for MAO-A) and [18F]FAZIN3 (binds to MAO-A), we have compared MAO-A in anterior cingulate in AD and control (CN) subjects. Our preliminary findings show >100% increase of MAO-A in anterior cingulate in postmortem AD brain subjects, and this increase in MAO-A positively correlated with increases in Tau, Aβ and TSPO. This may suggest greater neurotransmitter breakdown, increased production of reactive oxygen species, potentially causing protein degradation, aggregation and inflammation in AD. In order to ascertain a role of MAO-A in AD and compliment current imaging approaches in understanding Aβ and NFT accumulation in AD, we propose to carry out a detailed postmortem study in AD subjects to confirm MAO-A upregulation. Our goal is to examine anterior cingulate and hippocampus in AD and CN subjects, two brain regions where MAO-A has been studied with [11C]Harmine. In addition to [18F]FAZIN3 and [18F]FEH, we will also use [3H]Harmine (chemically identical to [11C]Harmine, except for the radioisotope). Positive findings with [3H]Harmine will support and provide impetus for PET studies in AD using [11C]Harmine, without much delay, since it is already approved for human use. For the two brain regions, comparisons between the biomarkers will be carried out to support the hypothesis that MAO-A is upregulated in AD and positively correlated with Tau, Aβ and TSPO measures of the same subjects. Impact of our findings will support PET imaging studies of MAO-A in AD subjects and may have the potential for AD drug development of MAO-A inhibitors for therapeutic purposes.

单胺氧化酶 A 作为阿尔茨海默病新生物标志物的评价 项目概要 此应用程序是对 PAR-19-071“阿尔茨海默病及其相关当前主题的研究”的回应 相关痴呆症（ADRD）”。阿尔茨海默病（AD）是一种以 Aβ 为特征的神经退行性疾病 斑块聚集和 Tau 蛋白配对螺旋丝导致大脑中的神经原纤维缠结 (NFT)。 磷酸化 Tau 异构体（pTau181 和 pTau181）的无创脑成像方法和外周测量 pTau217) 正在成为 AD 的可靠标记。除了这些生物标志物之外，易位蛋白 (TSPO) 作为炎症的标志物也正在努力获得全面的了解 疾病病因学。成像方法在理解 AD 中 NFT 积累方面发挥着关键作用 内嗅皮层和海马体，扩散到颞叶皮层，随后到达新皮层。 单胺氧化酶 A (MAO-A) 是一种存在于神经元中的线粒体酶，可将单胺脱氨 神经递质。 MAO-A 的上调可引起氧化应激，导致神经退行性变。现在， 目前尚未有关于 AD 患者 MAO-A 的 PET 成像研究报道。 [11C]Harmine，一种 MAO-A 宠物 放射性示踪剂已用于抑郁症的人类研究，但在 AD 方面尚无报道。在放射自显影中 使用 [18F]FEH（MAO-A 去氢骆驼蓬碱的类似物）和 [18F]FAZIN3（与 MAO-A 结合）进行研究，我们有 比较了 AD 和对照 (CN) 受试者前扣带回的 MAO-A。我们的初步调查结果显示 >100% 死后 AD 大脑受试者前扣带回 MAO-A 的增加，以及 MAO-A 的增加 与 Tau、Aβ 和 TSPO 的增加呈正相关。这可能表明神经递质更多 分解，活性氧产生增加，可能导致蛋白质降解， AD 中的聚集和炎症。为了确定 MAO-A 在 AD 中的作用并补充电流 为了理解 AD 中 Aβ 和 NFT 积累的成像方法，我们建议进行详细的研究 AD 受试者尸检研究证实 MAO-A 上调。我们的目标是检查前扣带回 AD 和 CN 受试者的海马体是用 [11C]Harmine 研究 MAO-A 的两个大脑区域。在 除了[18F]FAZIN3和[18F]FEH，我们还将使用[3H]Harmine（化学性质与[11C]Harmine相同， 放射性同位素除外）。 [3H]Harmine 的积极发现将为 PET 提供支持和推动 使用 [11C]Harmine 进行 AD 的研究没有太多延迟，因为它已经被批准用于人类。对于两个人来说 脑区域，生物标志物之间的比较将被进行以支持 MAO-A 的假设 在 AD 中表达上调，并与同一受试者的 Tau、Aβ 和 TSPO 测量呈正相关。的影响 我们的研究结果将支持 AD 受试者中 MAO-A 的 PET 成像研究，并且可能具有 AD 药物的潜力 开发用于治疗目的的 MAO-A 抑制剂。