White matter damage in Alzheimer?s disease: New cellular targets and mechanisms

阿尔茨海默病中的白质损伤：新的细胞靶点和机制

• 批准号: 7577523
• 负责人: MARK D NOBLE
• 金额: $ 16.36万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577523
• 关键词: Advanced Glycosylation End Products; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Antioxidants; Brain; Breeding; Cell Death; Cell Death Induction; Cell Survival; Cell division; Cell physiology; Cells; Cessation of life; Crossbreeding; Degradation Pathway; Disease; Dose; Event; Exposure to; Glutathione Disulfide; Goals; Hippocampus (Brain); Human; In Vitro; Individual; Lead; Maintenance; Mediating; Mediator of activation protein; Molecular; Mus; Myelin; Neuraxis; Neurons; Normal Cell; Oligodendroglia; Oxidation-Reduction; Pathogenesis; Pathology; Pathway interactions; Peptides; Phosphotransferases; Play; Premature Mortality; Protein Tyrosine Kinase; Proteins; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Regulatory Pathway; Research; Role; Signal Transduction; Site; Stem cells; Stimulus; Sum; Testing; Toxic effect; Transgenic Mice; antioxidant therapy; base; cell type; cellular targeting; cytotoxic; improved; insight; member; myelination; novel; oligodendrocyte lineage; overexpression; prevent; progenitor; protective effect; public health relevance; receptor; repaired; research study; src-Family Kinases; ubiquitin-protein ligase; white matter; white matter damage

DESCRIPTION (provided by applicant): The goal of this "exploratory" application is to provide a novel mechanistic understanding of vulnerability to amyloid (A ¿) protein, and of the pathways through which A¿ disrupts function of those cells critical in maintenance of normal myelination. We have recently discovered a novel regulatory pathway that provides a sequential linkage between oxidative changes and control of cell signaling. In this pathway, increases in oxidative status caused by exposure of cells to chemically diverse substances with pro-oxidant activity cause activation of Fyn kinase. This leads to activation of c-Cbl, an E3 ubiquitin ligase that is a target of Fyn. Activation of c-Cbl leads to ubiquitylation of its target proteins, which include among them a subset of receptor tyrosine kinases (RTKs). As a result of their interaction with c-Cbl, degradation of these RKTs is enhanced, leading to a suppression of downstream signaling. As a consequence of this degradation, downstream activation of such signaling mediators as Erk1/2 and Akt are suppressed. As one would predict from such an effect, cell division is suppressed and cell survival may also be impaired. We propose to now test the hypothesis that activation of the Fyn/c-Cbl pathway plays an important role in amyloid (A¿) toxicity. The experiments proposed focus on the effects of A¿ peptides on oligodendrocytes and their progenitor cells, due to the importance of myelin damage in AD pathology. Moreover, as the Fyn/c- Cbl hypothesis also predicts that exposure to sublethal concentrations of pro-oxidant stimuli will suppress cell division, we will further test the hypothesis that A¿ peptides are cytotoxic for oligodendrocytes but also suppress division of the progenitors from which they are generated. If this prediction is correct, this would indicate that A¿ both damages myelin-forming cells and suppresses the cell division required for repair. This research thus proposes a new molecular pathway by which A¿ affects cell function. Several studies have previously suggested an important role of Fyn in the pathogenesis of AD. Our studies will provide novel insights into the mechanism by which Fyn activation may disrupt cellular function in AD. Aim 1 tests the hypothesis that exposure of oligodendrocytes and their progenitors to A¿ causes activation of the redox/Fyn/c-Cbl pathway, degradation of RTKs that are c-Cbl targets, and selective suppression of downstream signaling events from these RTKs. This is associated with, depending on the type and concentration of A¿ and the cell type examined, suppression of progenitor cell division (at sublethal doses) and induction of progenitor cell and/or oligodendrocyte death at higher concentrations. Aim 2 tests the hypothesis that activation of the Fyn/c-Cbl pathway is functionally important in A¿ -mediated suppression of cell division and/or induction of cell death in the oligodendrocyte lineage. Aim 3 tests the hypothesis that anti-oxidants and trophic factors that protect against toxic effects of A¿ suppress A¿ -mediated activation of the redox/Fyn/c-Cbl pathway, thus providing a novel potential site of action for the protective effects of anti-oxidants in AD. PUBLIC HEALTH RELEVANCE: This research provides novel insights into the means by which amyloid ¿ protein causes damage to the central nervous system in Alzheimer's disease. Our studies identify a novel molecular pathway by which amyloid ¿ protein disrupts cell function, new insights into the pathogenesis of the extensive damage to myelinated tracts in this disease, and a new understanding of means by which anti-oxidant therapy protects from the effects of amyloid ¿ protein. This research will help in identifying new means of protecting against amyloid ¿ toxicity.

描述（由申请人提供）：该“探索性”应用的目标是提供对淀粉样蛋白 (A¿) 的脆弱性以及 A¿ 的途径的新机制理解。我们最近发现了一种新的调节途径，它提供了氧化变化和细胞信号传导控制之间的顺序联系，在该途径中，由于细胞暴露于不同的化学物质而导致氧化状态增加。具有促氧化活性的物质会激活 Fyn 激酶，从而激活 c-Cbl，而 c-Cbl 是 Fyn 的靶标 E3 泛素连接酶。其靶蛋白（其中包括受体酪氨酸激酶 (RTK)）的泛素化由于与 c-Cbl 的相互作用而增强，从而导致下游信号传导受到抑制。由于这种降解，Erk1/2 和 Akt 等信号传导介质的下游激活受到抑制，正如人们从这种效应中预测的那样，细胞分裂受到抑制，细胞存活也可能受到损害。 Fyn/c-Cbl 途径的 Fyn/c-Cbl 通路在淀粉样蛋白 (A¿ ）毒性。建议的实验重点是A¿的影响。由于髓磷脂损伤在 AD 病理学中的重要性，Fyn/c-Cbl 假说也预测暴露于亚致死浓度的促氧化剂刺激物会抑制细胞分裂，因此我们研究了少突胶质细胞及其祖细胞上的肽。假设 A?肽对少突胶质细胞具有细胞毒性，但也会抑制产生它们的祖细胞的分裂，如果这个预测是正确的，这将表明 A¿两者都会损害髓磷脂形成细胞并抑制修复所需的细胞分裂，因此这项研究提出了 A¿之前的一些研究表明 Fyn 在 AD 发病机制中发挥着重要作用，我们的研究将为 Fyn 激活可能破坏 AD 细胞功能的机制提供新的见解。他们的祖先是A¿导致氧化还原/Fyn/c-Cbl 途径的激活、c-Cbl 靶标 RTK 的降解以及这些 RTK 下游信号传导事件的选择性抑制，这与 A¿ 的类型和浓度有关。目标 2 测试了 Fyn/c-Cbl 途径的激活在 A 中具有重要功能的假设。 ¿目标 3 测试了抗氧化剂和营养因子可防止 A¿ 的毒性作用的假设。抑制A¿ - 介导氧化还原/Fyn/c-Cbl 途径的激活，从而为抗氧化剂在 AD 中的保护作用提供了一个新的潜在作用位点。 公共健康相关性：这项研究为淀粉样蛋白的作用提供了新的见解。蛋白质对阿尔茨海默氏病的中枢神经系统造成损害，我们的研究发现了淀粉样蛋白的一种新分子途径。蛋白质破坏细胞功能，对这种疾病中髓鞘纤维束广泛损伤的发病机制的新见解，以及对抗氧化疗法防止淀粉样蛋白影响的方法的新认识 ¿这项研究将有助于确定预防淀粉样蛋白的新方法。毒性。