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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

基本信息

批准号：
7644236
负责人：
Yong Shen
金额：
$ 2.55万
依托单位：
BANNER SUN HEALTH RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7644236
关键词：
Affect Age Age-Months Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloidosis Apoptosis Aspartic Endopeptidases Brain Cells Cerebral cortex Cessation of life Cleaved cell Complex Condition Data Dementia Deposition Exhibits Figs - dietary Generations Genetic Hippocampus (Brain)Human Immune system In Vitro Knockout Mice Link Mediating Membrane Membrane Proteins Messenger RNA Modality Mus Mutate Mutation NGFR Protein Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Numbers Pathology Peptide Fragments Peptides Play Production Protein Overexpression Proteins Proteolytic Processing Receptor Activation Regulation Reporting Resistance Role Senile Plaques Signal Pathway Signal Transduction Synapses TNF gene Therapeutic Toxic effect Transgenic Mice Wild Type Mouse amyloid precursor protein processing apoptotic protease-activating factor 1 beta-site APP cleaving enzyme 1 calbindin in vivo neuron apoptosis neuron loss neurotoxic nicastrin protein novel presenilin prevent protective effect receptor secretase transcriptional coactivator p75 tumor necrosis factor receptor 1A

项目摘要

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（申请人提供）：肿瘤坏死因子I型受体（Tumor necrosis factor type I receptor， TNFRI）是一种死亡受体，介导细胞凋亡，在神经系统和免疫系统的相互作用中起重要作用。死亡受体激活与信号级联介导的神经元死亡在神经退行性疾病脑中的直接联系仍不确定。我们最近证明，淀粉样蛋白- β (Abeta)是阿尔茨海默病（AD）脑斑块的主要成分，可诱导神经元凋亡，这是通过改变凋亡蛋白酶激活因子（Apaf-1）的表达介导的，而凋亡蛋白酶激活因子（Apaf-1）的表达反过来诱导NF-KB的激活。与野生型（WT）小鼠相比，Apaf-1突变或TNFRI缺失的神经元中NF-KB激活较少，表明TNF死亡受体级联是Abeta诱导的体外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APP小鼠TNF死亡受体的遗传抑制可能减少ad样病理，最终防止神经元丢失。