Ceramide-induced cell death in neurodegeneration

描述（由申请人提供）：阿尔茨海默病（Alzheimer's disease， AD）以海马神经元进行性丧失为特征，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被称为“斑块”和“缠结”的蛋白质聚集体的积聚引起的。星形胶质细胞在神经元细胞死亡中的作用尚不清楚。最近，我们发现来自AD小鼠模型（PS1M146V）的星形胶质细胞表达的前列腺凋亡反应-4 （PAR-4）水平比野生型星形胶质细胞高9倍。PAR-4是一种抑制非典型PKC6/的促凋亡蛋白；（aPKC）与神经酰胺结合。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凋亡敏感，从而导致阿尔茨海默病的神经退行性变。非常令人兴奋的新结果表明，来自PS1小鼠的海马组织中富含不同的神经酰胺物种，这些神经酰胺物种可诱导PS1星形胶质细胞凋亡，但在野生型细胞中却没有。这一结果清楚地表明PS1星形胶质细胞对神经酰胺升高特别敏感。此外，在AD患者的海马中，淀粉样斑块被星形胶质细胞包围，显示神经酰胺和PAR-4的共同升高。许多星形胶质细胞凋亡。我们现在将确定神经酰胺的升高是如何被激活的（Specific Aim 1），神经酰胺和PAR-4的联合升高是如何诱导细胞凋亡的（Specific Aim 2），以及如何防止这种共同升高和细胞凋亡诱导（Specific Aim 3）。意义：我们首次发现来自AD脑的星形胶质细胞被神经酰胺诱导的细胞凋亡特异性清除。采用体外和体内联合模型（Psen1和APP/PS1星形胶质细胞和小鼠）；我们的研究将为星形胶质细胞和神经元的凋亡提供一种新的保护策略。这一策略对阿尔茨海默病的治疗具有重要意义

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.