p75 -mediated protection from amyloid neurodegeneration

p75 介导的淀粉样神经变性保护

• 批准号: 7291518
• 负责人: JULIET KLASING KNOWLES
• 金额: $ 4.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2009-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291518
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Binding; Biological Assay; Cell Death; Cell Line; Cessation of life; Computers; Development; Event; Fellowship; Hippocampus (Brain); Impaired cognition; In Vitro; Individual; Investigation; Laboratories; Ligands; MAPK8 gene; Mediating; Mediator of activation protein; Mus; NGFR Protein; Names; Nerve Degeneration; Neurons; Pathogenesis; Pathway interactions; Purpose; Role; Screening procedure; Signal Transduction; Tg2576; Therapeutic; Thinking; Toxic effect; Transgenic Organisms; base; improved; in vivo; mouse model; neuroprotection; neurotoxic; novel; prevent; progressive neurodegeneration; receptor; research study; small molecule; tau phosphorylation; transcriptional coactivator p75

DESCRIPTION (provided by applicant): No approved therapy can prevent the progressive neurodegeneration of Alzheimer's disease (AD). Accumulation of the neurotoxic amyloid-beta (A-beta) peptide is thought to be pathogenic, though underlying mechanisms are incompletely understood. Studies in cell lines suggest A-beta binds to the p75 neurotrophin receptor to activate deleterious signals and induce cell death. Our laboratory identified novel, nonpeptide small molecule ligands of the p75 neurotrophin receptor, C24 and C31, which bind to p75 and activate survival promoting signaling, and which protect primary neurons from A-beta-induced degeneration. If A-beta toxicity in neurons is mediated, in part, by p75, C24 and C31 could inhibit this interaction. Alternatively, survival signaling activated by C24 and C31 could downregulate deleterious A-beta signaling to prevent degeneration. We will determine the role of p75 in A-beta induced degeneration, using p75 -/- neurons, in vitro and in vivo. In addition, we will determine whether C24 and C31 inhibit deleterious A-beta signaling and degeneration, in vitro and [in transgenic mouse models of AD]. This will contribute to understanding AD pathogenesis and to the development of improved therapeutic strategies.

描述（由申请人提供）： 没有批准的治疗可以预防阿尔茨海默病（AD）的进行性神经变性。神经毒性淀粉样蛋白-β（A-β）肽的积累被认为是致病的，尽管其潜在的机制还不完全清楚。对细胞系的研究表明，A-β与p75神经营养因子受体结合，激活有害信号并诱导细胞死亡。我们的实验室鉴定了p75神经营养因子受体的新型非肽小分子配体C24和C31，它们与p75结合并激活促进存活的信号传导，并保护原代神经元免受A-β诱导的变性。如果神经元中的A-β毒性部分由p75介导，则C24和C31可以抑制这种相互作用。或者，由C24和C31激活的存活信号传导可以下调有害的A-β信号传导以防止退化。我们将使用p75 -/-神经元，在体外和体内确定p75在A-β诱导的变性中的作用。此外，我们将确定C24和C31是否在体外和[在AD转基因小鼠模型中]抑制有害的A-β信号传导和变性。这将有助于了解AD的发病机制，并改善治疗策略的发展。