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 项目摘要 本申请是对PAR-19-071“阿尔茨海默病及其相关疾病的当前主题研究”的回应。 相关性痴呆（ADRD）。阿尔茨海默病（Alzheimer's disease，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脑中的神经元缠结（NFT）。 非侵入性脑成像方法和磷酸化Tau同种型（pTau 181和pTau 182）的外周测量 pTau 217）成为AD的可靠标记。除了这些生物标志物，转运蛋白（TSPO） 作为炎症的标志物，也在努力获得对炎症的全面了解。 疾病病因。影像学方法在理解AD中NFT积累方面起着关键作用， 内嗅皮层和海马，扩散到颞叶皮层，随后扩散到新皮层。 单胺氧化酶A（MAO-A）是一种存在于神经元中的线粒体酶， 神经传递素MAO-A的上调可引起氧化应激，导致神经变性。目前， 还没有关于AD患者中MAO-A的PET成像研究的报道。[11C]Harmine，MAO-A PET 放射性示踪剂已被用于人类抑郁症的研究，但没有报告存在于AD。放射自显影 使用[18 F]FEH（MAO-A的骆驼蓬碱类似物）和[18 F] FAZIN 3（与MAO-A结合）的研究， 比较了AD和对照（CN）受试者前扣带回中的MAO-A。我们的初步调查结果显示>100% AD患者死后前扣带回MAO-A增加， 与Tau、Aβ和TSPO的增加呈正相关。这可能表明更大的神经递质 分解，增加活性氧的产生，可能导致蛋白质降解， 聚集和炎症。为了确定MAO-A在AD和补充电流中的作用 在了解AD中Aβ和NFT积聚的成像方法中，我们建议进行详细的 在AD受试者中进行尸检研究以证实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，这是使用[11 C]Harmine研究MAO-A的两个大脑区域。在 除了[18F] FAZIN 3和[18F]FEH之外，我们还将使用[3 H]去氢骆驼蓬碱（化学上与[11 C]去氢骆驼蓬碱相同， 除了放射性同位素）。[3 H]Harmine的积极发现将支持并推动PET 使用[11 C]Harmine的AD研究，没有太多延迟，因为它已经被批准用于人类使用。两 大脑区域，将进行生物标志物之间的比较，以支持MAO-A是 在AD中上调，并与相同受试者的Tau、Aβ和TSPO测量值呈正相关。影响 我们的研究结果将支持AD患者MAO-A的PET成像研究，并可能具有开发AD药物的潜力。 开发用于治疗目的的MAO-A抑制剂。