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.

项目概要阿尔茨海默病 (AD) 是最常见的神经退行性疾病，也是导致神经退行性疾病的主要原因痴呆症影响了超过 600 万美国人，而 AD 的病理特征包括 β-淀粉样蛋白。斑块和 tau 神经原纤维缠结，tau 蛋白过度磷酸化（“前缠结”）的出现去甲肾上腺素能蓝斑 (LC) 和 LC 体积损失是第一个可检测到的 AD 样变化。人类大脑，并且与 AD 前驱症状的发生一致，例如觉醒/睡眠灾难性 LC 之前存在紊乱、焦虑、抑郁和激动。当记忆丧失明显时，退化在疾病后期是普遍存在的。 AD 领域的两个关键问题：（1）为什么 LC 神经元容易发生病理变化并在 AD，以及（2）它们的功能障碍和退化如何导致前驱症状和认知症状。儿茶酚胺神经元（包括 LC）在神经黑色素 (NM)（一种色素）的表达方面具有独特性由儿茶酚胺代谢物、重金属、脂质和蛋白质聚集体组成，是一种重要的 NM。 AD 中 LC 神经元的生物标志物，因为 NM 敏感 MRI 对比被用作 LC 完整性的代表。因为 NM 不是在啮齿动物中自然产生的，所以我们对它如何产生神经元知之甚少我们开发了一种表达人类酪氨酸酶 (hTyr) 的病毒载体，它可以驱动 NM 在目标 1 中，我们将确定 NM 如何影响 LC 完整性。在目标 2 中，我们将评估 NM 如何影响 LC 完整性。 NM 诱导的 LC 放电和基因表达改变，以及 LC 功能的这些变化如何触发与 AD 前驱症状和认知症状相关的行为在目标 3 中，我们将操纵各个方面。 NE 合成/代谢和 tau 蛋白的分析，以确定 NM 积累和毒性的修饰因素。这些目标将首次测试 NM 和 LC 变性与功能之间的因果关系，为预防 AD 中 LC 细胞丢失以及行为和认知缺陷的新疗法奠定了基础。