Contribution of neuromelanin to selective vulnerability of locus coeruleus neurons in Alzheimer's disease

神经黑色素对阿尔茨海默氏病蓝斑神经元选择性脆弱性的贡献

基本信息

批准号：
10525513
负责人：
DAVID WEINSHENKER
金额：
$ 153.16万
依托单位：
EMORY UNIVERSITY
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：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525513
关键词：
Affect Agitation Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease test American Animal Model Animals Anxiety Apoptosis Appearance Arousal Autopsy Behavior Behavioral Behavioral Symptoms Biological Markers Brain Brain region Catecholamines Cell Death Cells Chromatography Clinical Research Cognition Cognitive Cognitive deficits Cytoplasmic Granules Dementia Development Disease Electron Microscopy Electrophysiology (science)Enzymes Fiber Fontana-Masson stain Foundations Functional disorder Gene Expression Gene Expression Alteration Goals Heavy Metals Human Image Immunohistochemistry Impaired cognition Inflammation Link Lipids Liquid substance Longevity Magnetic Resonance Imaging Mediating Melanins Memory Loss Memory impairment Mental Depression Metabolism Methods Monophenol Monooxygenase Morphology Mus Nerve Degeneration Neurobehavioral Manifestations Neurobiology Neurodegenerative Disorders Neurons Neurotoxins Norepinephrine Pathologic Pathology Performance Pharmacology Phenotype Pigmentation physiologic function Pigments Primates Production Proxy Quality of life Research Rodent Rodent Model Role Senile Plaques Skin Sleep disturbances Slice Structure Study models Substantia nigra structure Symptoms Testing Time Tissues Toxic effect Toxin Viral Viral Vector Visualization base cell type genetic approach histological stains human old age (65+)hyperphosphorylated tau improved in vivo insight locus ceruleus structure neuroinflammation neuromelanin neuropathology noradrenergic novel novel marker novel therapeutics prevent prodromal Alzheimer&apos s disease protein aggregation synergism tau Proteins tau aggregation transcriptome sequencing transmission process

项目摘要

Project Summary Alzheimer’s disease (AD) is the most common form of neurodegenerative disease and the leading cause of dementia, affecting over 6 million Americans. While the pathological hallmarks of AD include β-amyloid plaques and tau neurofibrillary tangles, the appearance of hyperphosphorylated (“pretangle”) tau in the noradrenergic locus coeruleus (LC) and loss of LC volume are the first detectable AD-like changes in the human brain, and coincide with the onset of prodromal AD symptoms such as including arousal/sleep disturbances, anxiety, depression, and agitation prior to frank cognitive impairment. Catastrophic LC degeneration is ubiquitous later in disease when memory loss is evident. The goal of this proposal is to answer two critical questions in the AD field: (1) Why are LC neurons vulnerable to developing pathology and dying in AD, and (2) how does their dysfunction and degeneration contribute to prodromal and cognitive symptoms. Catecholamine neurons, including the LC, are unique in their expression of neuromelanin (NM), a pigment comprised of catecholamine metabolites, heavy metals, lipids, and protein aggregates. NM is an important biomarker of LC neurons in AD, as NM-sensitive MRI contrast is used as a proxy of LC integrity. However, because NM is not naturally produced in rodents, we know very little about how it might make neurons vulnerable in AD. We have developed a viral vector expressing human tyrosinase (hTyr), which drives NM production in the mouse LC. In Aim 1, we will determine how NM affects LC integrity. In Aim 2, we will assess LC firing and gene expression alterations induced by NM, and how these changes in LC function trigger behaviors relevant to prodromal and cognitive symptoms of AD. In Aim 3, we will manipulate various aspects of NE synthesis/metabolism and tau to identify modifiers of NM accumulation and toxicity. Completion of these aims will test, for the first time, causal relationships between NM and LC degeneration and function, laying the foundation for novel therapies that prevent LC cell loss and behavioral and cognitive deficits in AD.

项目摘要阿尔茨海默氏病（AD）是神经退行性疾病的最常见形式，是痴呆症，影响超过600万美国人。而AD的病理标志包括β-淀粉样蛋白斑块和tau神经纤维缠结，在the中的高磷酸化（“ pripangle”）tau的出现去肾上腺素能基因座（LC）和LC量损失是第一个可检测的广告样变化人脑，与前驱AD症状的发作相吻合，例如包括唤醒/睡眠在弗兰克认知障碍之前，骚乱，动画，抑郁和躁动。灾难性LC 当记忆力丧失是证据时，堕落在疾病中无处不在。该提议的目的是回答广告领域中的两个关键问题：（1）为什么LC神经元很容易发生病理学和死亡 AD，以及（2）它们的功能障碍和变性如何导致前驱和认知症状。儿茶酚胺神经元（包括LC）在神经苯胺（NM）的表达中是独一无二的完成儿茶酚胺代谢物，重金属，脂质和蛋白质骨料的完成。 NM是重要的 AD中LC神经元的生物标志物，因为NM敏感的MRI对比度被用作LC完整性的代理。然而，因为NM不是在啮齿动物中自然产生的，所以我们对它可能如何使神经元知之甚少在广告中脆弱。我们已经开发了一种表达人酪氨酸酶（HTYR）的病毒载体，该毒素驱动NM 在小鼠LC中产生。在AIM 1中，我们将确定NM如何影响LC完整性。在AIM 2中，我们将评估 NM诱导的LC触发和基因表达改变以及LC功能中的这些变化如何触发与AD的前驱和认知症状相关的行为。在AIM 3中，我们将操纵各个方面 NE合成/代谢和TAU的识别，以鉴定NM积累和毒性的修饰符。完成这些目标将首次测试NM与LC变性与功能之间的因果关系，为预防AD中LC细胞丧失以及行为和认知缺陷的新型疗法奠定基础。