Ceramide-induced cell death in neurodegeneration

神经退行性变中神经酰胺诱导的细胞死亡

• 批准号: 8531806
• 负责人: Erhard Bieberich
• 金额: $ 27.93万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531806
• 关键词: APP-PS1; Affect; Alzheimer' s Disease; Anabolism; Apoptosis; Apoptotic; Astrocytes; BCL2 gene; Brain; Cell Death; Cell Survival; Ceramides; Cessation of life; Cytokine Activation; Data; Disease; Disease Progression; Generations; Hippocampus (Brain); In Vitro; Induction of Apoptosis; Mediating; Memory Loss; Metabolism; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Patients; Principal Investigator; Prostate; Reporting; Role; Senile Plaques; Signal Pathway; Signal Transduction; Sphingolipids; Sphingomyelinase; Sphingomyelins; Stem cells; Testing; Time; Tissues; United States; analog; brain tissue; cell type; cytokine; dihydroceramide desaturase; in vivo; in vivo Model; knock-down; mouse model; neuron apoptosis; neuron loss; novel; novel strategies; prevent; pro-apoptotic protein; programs; protein aggregate; public health relevance; response

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by the progressive loss of neurons in the hippocampus ultimately leading to total memory loss and death of the patient. Neuronal cell death is thought to be caused by the build-up of protein-aggregates termed "plaques" and "tangles". The role of astrocytes in neuronal cell death is only marginally understood. Most recently, we have found that astrocytes from a mouse model of AD (PS1M146V) express 9-fold higher levels of prostate apoptosis response-4 (PAR-4) than wild-type astrocytes. PAR-4 is a pro-apoptotic protein that inhibits atypical PKC6/; (aPKC) when associated with ceramide. Our main hypothesis is that elevation of PAR-4 sensitizes astrocytes toward ceramide-induced apoptosis, which leads to neurodegeneration in AD. Very exciting new results show that hippocampal tissue from the PS1 mouse is enriched in distinct ceramide species that induce apoptosis in PS1 astrocytes, but not in wild-type cells. This result clearly demonstrates that PS1 astrocytes are specifically sensitive to ceramide elevation. Further, in hippocampus from AD patients, amyloid plaques are surrounded by astrocytes that show co-elevation of ceramide and PAR-4. Many of these astrocytes are apoptotic. We will now determine how ceramide elevation is activated (Specific Aim 1), how the combined elevation of ceramide and PAR-4 induces apoptosis (Specific Aim 2), and how this co-elevation elevation and apoptosis induction can be prevented (Specific Aim 3). SIGNIFICANCE: We have shown for the first time that astrocytes from AD brain are specifically eliminated by ceramide-induced apoptosis. Using a combination of in vitro and in vivo models (Psen1 and APP/PS1 astrocytes and mice); our study will develop a novel strategy to protect astrocytes and neurons from apoptosis. This strategy will be highly significant for treatment of AD PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating disease affecting 5 million people in the United States. Progressive memory loss and ultimately, cell death of neurons is caused by the build-up of protein aggregates called "plaques" and "tangles". We have found, for the first time, that in a mouse model of AD, the lipid ceramide is enriched and specifically induces cell death in astrocytes. We hypothesize that dying astrocytes fail to support neurons, which amplifies the degeneration of neurons in AD. Our data strongly suggest that blocking the accumulation of ceramide will be instrumental in preventing loss of neurons in AD.

描述(申请人提供)：阿尔茨海默病(AD)的特征是海马区神经元的进行性丧失，最终导致患者完全记忆丧失和死亡。神经细胞死亡被认为是由蛋白质聚合体的积聚引起的，这些蛋白质聚集物被称为“斑块”和“缠结”。星形胶质细胞在神经细胞死亡中的作用还知之甚少。最近，我们发现AD小鼠模型(PS1M146V)的星形胶质细胞表达的前列腺癌凋亡反应-4(PAR-4)水平是野生型星形胶质细胞的9倍。PAR-4是一种促凋亡蛋白，当与神经酰胺结合时，可抑制非典型的PKC6/(APKC)。我们的主要假设是PAR-4的升高使星形胶质细胞对神经酰胺诱导的细胞凋亡敏感，从而导致AD的神经变性。非常令人兴奋的新结果表明，来自PS1小鼠的海马区组织富含诱导PS1星形胶质细胞凋亡的不同神经酰胺种类，而不是野生型细胞。这一结果清楚地表明PS1星形胶质细胞对神经酰胺的升高具有特异性的敏感性。此外，在AD患者的海马区，淀粉样斑块被星形胶质细胞包围，星形细胞显示神经酰胺和PAR-4共同升高。这些星形胶质细胞中有许多是凋亡性的。我们现在将确定神经酰胺上调是如何激活的(特定目标1)，神经酰胺和PAR-4联合上调如何诱导细胞凋亡(特定目标2)，以及如何防止这种共同上调和凋亡诱导(特定目标3)。意义：我们首次表明，神经酰胺诱导的细胞凋亡可以特异性地消除AD大脑中的星形胶质细胞。结合使用体外和体内模型(PSEN1和APP/PS1星形胶质细胞和小鼠)，我们的研究将开发一种新的策略来保护星形胶质细胞和神经元免受凋亡的影响。这一策略将对AD的治疗具有重要意义 公共卫生相关性：阿尔茨海默病(AD)是一种毁灭性的疾病，在美国有500万人受到影响。进行性记忆丧失，最终导致神经元细胞死亡的原因是蛋白质聚集，称为“斑块”和“缠结”。我们首次发现，在阿尔茨海默病的小鼠模型中，脂质神经酰胺被丰富，并特异性地诱导星形胶质细胞死亡。我们假设死亡的星形胶质细胞不能支持神经元，这放大了AD中神经元的退化。我们的数据有力地表明，阻断神经酰胺的积累将有助于防止AD神经元的丢失。