权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结