Acid Ceramidase in Alzheimers Disease

阿尔茨海默病中的酸性神经酰胺酶

基本信息

批准号：
10646906
负责人：
CHRISTINA VOELKEL-JOHNSON
金额：
$ 7.55万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646906
关键词：
Acids Adipocytes Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient American Animal Model Animals Astrocytes Behavior Brain Brain Diseases Cell Aging Cell Death Cells Cellular biology Ceramides Clinic Complex Cost of Illness Dementia Development Diagnosis Disease Disease Progression Disease model Endothelial Cells Enzymes Excision Family Farber&apos s lipogranulomatosis Functional disorder Future Growth Healthcare Systems Hydrolysis Impaired cognition Impairment Inflammation Knock-out Knockout Mice Lipids Memory Memory impairment Metabolism Microglia Modeling Mouse Strains Mus Nerve Degeneration Neurofibrillary Tangles Neuronal Dysfunction Neurons Neuropathy Pathology Patients Persons Phosphotransferases Proliferating Reaction Reporting Role Signal Pathway Signal Transduction Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Sphingolipids Sphingosine Stress Testing United States Vertebral column amyloid peptide angiogenesis brain tissue burden of illness cognitive function cognitive skill combat conditioned fear cost dementia risk enzyme activity exosome galactosylgalactosylglucosylceramidase improved insight lipid I liquid chromatography mass spectrometry migration neuroinflammation neuropathology normal aging novel novel therapeutic intervention object recognition senescence sphingosine 1-phosphate tau Proteins therapeutic development therapy development

项目摘要

PROJECT SUMMARY The neurodegenerative condition known as Alzheimer’s disease (AD) is increasingly placing a burden on our health care system, patients, and their families. One factor that appears to contribute to neurodegeneration, and distinguishes the development of AD from normal ageing, is cellular senescence. However, the mechanisms, causes and consequences of cellular senescence in AD and associated neuropathology remain poorly understood. A recent study demonstrated a role for the lysosomal sphingolipid enzyme acid ceramidase (AC) in ageing and senescence. Deregulation of sphingolipid metabolism has been documented in AD pathology, but the role of AC has not been explored in animal models. Depending on pH, AC catalyzes either forward or reverse reaction. Because primary lysosomal dysfunction and acidification impairment occurs AD, the increased pH potentially promotes the reverse activity of AC, which would increase the stress lipid ceramide and promote neuronal dysfunction. In this project we will test the hypothesis that acid ceramidase contributes to neurodegeneration associated with Alzheimer’s Disease. In specific aim 1, we will generate PDAPP and 5xFAD AD mice in which AC is deleted either in a neuron-specific or globally inducible manner. In specific Aim 2, we will determine how loss of AC function affects AD pathology and behavior in PDAPP and 5xFAD models. The use of neuron-specific and global AC deficient AD models will elucidate the role of the enzyme in neuronal cells and clarify how loss of AC in other cells contributes to the disease. Understanding the role of AC in AD has the potential for development of novel therapeutic strategies that combat this debilitating and costly disease.

项目摘要称为阿尔茨海默氏病（AD）的神经退行性疾病越来越多地将伯恩放在我们的身上医疗保健系统，患者及其家人。似乎有助于神经变性的一个因素，区分AD的发展与正常衰老的开发是细胞的感应。但是，机制， AD和相关神经病理学中细胞感应的原因和后果仍然很差理解。最近的一项研究表明，溶酶体鞘脂酶酸神经酰胺酶（AC）在衰老和感应。在AD病理学中已记录了鞘脂代谢的放松管制，但在动物模型中尚未探索AC的作用。根据pH，AC向前或反向催化反应。由于原发性溶酶体功能障碍和酸化障碍发生AD，因此pH值增加有可能促进AC的反向活性，这将增加应力脂质神经酰胺并促进神经元功能障碍。在这个项目中，我们将检验以下假设：酸性神经酶有助于神经变性与阿尔茨海默氏病有关。在特定目标1中，我们将生成PDAPP和5XFAD 以神经特异性或全球诱导方式删除AC的AD小鼠。在特定的目标2中，我们将确定AC功能的损失如何影响PDAPP和5XFAD模型中的AD病理和行为。这使用神经特异性和全局AC缺陷AD模型将阐明酶在神经元细胞中的作用并阐明其他细胞中AC的损失如何促进该疾病。了解AC在AD中的作用具有开发新型治疗策略的潜力，这些治疗策略与这种衰弱和昂贵的疾病作斗争。