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 这项申请是对PAR-19-071的响应，“关于阿尔茨海默病的当前主题及其研究 相关痴呆症(ADRD)“。阿尔茨海默病(AD)是一种以β为特征的神经退行性疾病 斑块聚集和Tau蛋白成对的螺旋细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)的无创性脑成像方法和外周测量 PTau217)正成为AD的可靠标志物。除了这些生物标志物，转位蛋白(TSPO) 作为炎症的标志，也在努力全面了解 疾病病因学。成像方法在了解AD早期NFT积聚方面发挥了关键作用 内嗅皮层和海马体，扩散到颞叶皮质，随后扩散到新皮质。 单胺氧化酶A(MAO-A)是一种存在于神经元中的线粒体酶，可使单胺脱氨基 神经递质。MAO-A的上调可导致氧化应激，导致神经退化。目前， 关于AD患者MAO-A的PET成像研究尚未见报道。[11C]哈敏，MAO-A宠物 放射性示踪剂已经用于人类抑郁症的研究，但在AD方面还没有报道。在放射自显影中 使用[18F]FEH(MAO-A的类似物)和[18F]FAZIN3(与MAO-A结合)的研究，我们有 比较AD组和对照组(CN)前扣带回MAO-A的表达。我们的初步调查结果显示&gt；100% 死后AD脑受试者前扣带回MAO-A的增加及MAO-A的增加 与Tau、Aβ、Tspo升高呈正相关。这可能意味着更多的神经递质。 分解，增加了活性氧的产生，可能导致蛋白质降解， 阿尔茨海默病中的聚集和炎症。为了确定MAO-A在AD和恭维潮流中的作用 影像方法在了解Aβ和NFT在AD中的积聚时，我们建议进行详细的 AD患者的尸检研究证实MAO-A上调。我们的目标是检查前扣带回和 AD和CN受试者的海马体，这两个大脑区域的MAO-A已经用[11C]Harmine进行了研究。在……里面 除了[18F]FAZIN3和[18F]FEH，我们还将使用[~3H]Harmine(化学上与[11C]Harmine相同， 除了放射性同位素)。[~3H]Harmine的阳性发现将支持和推动PET 在AD研究中使用[11C]Harmine，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 大脑区域，将进行生物标志物之间的比较，以支持MAO-A是 AD患者Tau、Aβ、TSPO呈正相关。影响 我们的发现将支持AD患者MAO-A的PET成像研究，并可能成为AD药物的潜在药物 治疗用MAO-A抑制剂的研究进展。