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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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.

评估单胺氧化酶A作为阿尔茨海默氏病的新生物标志物项目摘要该申请是对第19帕尔（Par-19-071）的回应，“关于阿尔茨海默氏病及其目前主题相关痴呆症（ADRD）。阿尔茨海默氏病（AD）是一种以Aβ为特征的神经退行性疾病斑块聚集和tau蛋白配对的螺旋丝，导致大脑中的神经纤维缠结（NFT）。磷酸化tau同工型的无创脑成像方法和外围度量（PTAU181和 PTAU217）正在成为AD的可靠标记。除了这些生物标志物，易位蛋白（TSPO）作为炎症的标志也正在努力获得全面的理解疾病病因。成像方法在理解NFT积累的广告中起着关键作用内嗅皮层和海马，分布在临时皮质上，然后扩散到新皮层。单胺氧化物A（MAO-A），一种在神经元中发现的线粒体酶，脱氨酸单胺神经递质。 MAO-A的上调会导致氧化应激导致神经退行性。现在，在AD患者中，尚无对MAO-A的宠物成像研究。 [11C] Harmine，Mao-A宠物放射性示例已用于人类抑郁症研究，但AD中没有任何报道。在放射自显影中使用[18F] FEH（MAO-A的Harmine类似物）和[18F] Fazin3（与MAO-A结合）的研究，我们有在AD和对照（CN）受试者中比较了MAO-A的前扣带回。我们的初步发现显示> 100％ MAO-A在尸体AD大脑受试者中的前扣带回中的增加，并且MAO-A的增加与Tau，Aβ和TSPO的增加相关。这可能表明更大的神经递质分解，活性氧的产生增加，可能导致蛋白质降解， AD的聚集和炎症。为了确定MAO-A在AD和合规性电流中的作用在理解Aβ和NFT积累的AD中的成像方法，我们建议进行详细的在AD受试者中验尸研究以确认MAO-A上调。我们的目标是检查前扣带回和 AD和CN受试者中的海马，这是两个大脑区域，其中MAO-A已研究了[11C] Harmine。在除[18f] fazin3和[18f] feh中，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的积极发现将支持并为PET提供动力使用[11C] Harmine进行AD的研究，毫不拖延，因为它已经被批准用于人类使用。对于两个大脑区域，将进行生物标志物之间的比较，以支持MAO-A是的假设在AD中进行更新，并与同一受试者的TAU，Aβ和TSPO测量正相关。影响我们的发现将支持AD受试者中MAO-A的PET成像研究，并可能具有AD药物的潜力用于治疗目的的MAO-A抑制剂的开发。