Acid Ceramidase in Alzheimers Disease

项目总结 被称为阿尔茨海默病(AD)的神经退行性疾病正日益给我们的 卫生保健系统、患者及其家人。一个似乎导致神经退化的因素，以及 阿尔茨海默病的发展不同于正常衰老，是细胞衰老。然而，这些机制， 阿尔茨海默病细胞衰老的原因和后果以及相关的神经病理学仍然很差 明白了。最近的一项研究表明，溶酶体鞘磷脂酶酸性神经酰胺酶(AC)在 衰老和衰老。神经鞘脂代谢的松弛在AD病理中已有文献记载，但 AC的作用还没有在动物模型中被探索。根据pH值的不同，AC催化正向或反向催化 反应。由于原发性溶酶体功能障碍和酸化损害发生在AD，因此升高的pH 潜在地促进AC的逆转活性，从而增加应激状态下的脂质神经酰胺，促进 神经元功能障碍。在这个项目中，我们将检验酸性神经酰胺酶对 与阿尔茨海默病相关的神经退行性变。在具体目标1中，我们将生成PDAPP和5xFAD 在AD小鼠中，AC以神经元特异性或全局可诱导的方式缺失。在具体目标2中，我们 将确定AC功能丧失如何影响PDAPP和5xFAD模型中的AD病理和行为。这个 使用神经元特异性和全局AC缺乏的AD模型将阐明该酶在神经细胞中的作用 并阐明其他细胞中AC的丢失是如何导致疾病的。了解AC在AD中的作用 有可能开发新的治疗策略，与这种虚弱和昂贵的疾病作斗争。

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.