Novel roles of TNF death receptor in amyloidosis in vivo

TNF死亡受体在体内淀粉样变性中的新作用

• 批准号: 7144283
• 负责人: Yong Shen
• 金额: $ 32.51万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144283
• 关键词: Alzheimer' s disease; age difference; amyloid proteins; amyloidosis; apoptosis; aspartic endopeptidases; calbindin; gene induction /repression; genetically modified animals; immunocytochemistry; isozymes; laboratory mouse; neural degeneration; neural transmission; neuritic plaques; pathologic process; receptor; transcription factor; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. We have recently demonstrated that amyloid-beta protein (Abeta) a major component of plaques in the Alzheimer's diseased (AD) brain, induces neuronal apoptosis and this was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of NF-KB. Abeta-induced neuronal apoptosis was reduced with lower Apaf-1 expression and little NF-KB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared to the cells from wild type (WT) mice, suggesting that the TNF death receptor cascade is required for Abeta induced neuron death in vitro. To expand and further study the mechanisms in vivo, we propose that genetic inhibition of the TNF death receptor in APP mice may reduce AD-like pathology and ultimately prevent neuronal loss.

描述（由申请方提供）：肿瘤坏死因子I型受体（TNFRI）是一种死亡受体，介导细胞凋亡，在神经系统和免疫系统之间的相互作用中起关键作用。死亡受体激活和信号级联介导的神经元死亡之间的直接联系与神经退行性疾病的大脑仍然没有定论。我们最近已经证明，淀粉样β蛋白（Abeta）的主要组成部分的斑块在阿尔茨海默氏病（AD）的大脑，诱导神经元凋亡，这是通过改变凋亡蛋白酶激活因子（Apaf-1）的表达，反过来诱导激活NF-κ B介导的。与来自野生型（WT）小鼠的细胞相比，在具有突变的Apaf-1或TNFRI缺失的神经元中，A β诱导的神经元凋亡随着较低的Apaf-1表达而减少，并且几乎没有发现NF-κ B活化，这表明TNF死亡受体级联是体外A β诱导的神经元死亡所必需的。为了扩大和进一步研究体内机制，我们提出，遗传抑制APP小鼠的TNF死亡受体可能会减少AD样病变，并最终防止神经元丢失。