Ceramide-induced cell death in neurodegeneration

描述（由申请人提供）：阿尔茨海默病（AD）的特征在于海马体中神经元的进行性损失，最终导致患者的完全记忆丧失和死亡。神经元细胞死亡被认为是由称为“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仅被边缘理解。最近，我们发现AD小鼠模型（PS1 M146 V）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是一种促凋亡蛋白，当与神经酰胺结合时，其抑制非典型PKC 6/i（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凋亡敏感，从而导致AD的神经退行性变。非常令人兴奋的新结果表明，来自PS1小鼠的海马组织富含诱导PS1星形胶质细胞凋亡的不同神经酰胺种类，但在野生型细胞中则不然。该结果清楚地表明，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，淀粉样蛋白斑块被显示神经酰胺和PAR-4共同升高的星形胶质细胞包围。这些星形胶质细胞中的许多是凋亡的。我们现在将确定神经酰胺升高是如何被激活的（具体目标1），神经酰胺和PAR-4的联合升高如何诱导细胞凋亡（具体目标2），以及如何预防这种共同升高和细胞凋亡诱导（具体目标3）。意义：我们首次发现AD脑星形胶质细胞被神经酰胺诱导的凋亡特异性清除。使用体外和体内模型（Psen 1和APP/PS1星形胶质细胞和小鼠）的组合;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于凋亡。这一策略对AD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