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¿) 蛋白脆弱性的新机制理解，以及 A¿ 破坏对维持正常髓鞘形成至关重要的细胞功能的途径。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。在此途径中，由于细胞暴露于具有促氧化活性的多种化学物质而导致氧化状态增加，从而导致 Fyn 激酶激活。这会导致 c-Cbl 的激活，c-Cbl 是一种 E3 泛素连接酶，是 Fyn 的靶标。 c-Cbl 的激活会导致其靶蛋白泛素化，其中包括受体酪氨酸激酶 (RTK) 的一个子集。由于它们与 c-Cbl 相互作用，这些 RKT 的降解增强，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。我们现在建议检验 Fyn/c-Cbl 途径的激活在淀粉样蛋白 (A¿) 毒性中发挥重要作用的假设。由于髓磷脂损伤在 AD 病理学中的重要性，实验建议重点关注 A¿ 肽对少突胶质细胞及其祖细胞的影响。此外，由于Fyn/c-Cbl假说还预测暴露于亚致死浓度的促氧化剂刺激物将抑制细胞分裂，因此我们将进一步检验以下假说：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。如果这一预测正确，则表明 A¿ 既会损害髓磷脂形成细胞，又会抑制修复所需的细胞分裂。因此，这项研究提出了 A¿ 影响细胞功能的新分子途径。此前已有多项研究表明 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。目标 1 检验以下假设：少突胶质细胞及其祖细胞暴露于 A¿ 会导致氧化还原/Fyn/c-Cbl 途径激活、c-Cbl 靶标 RTK 降解以及选择性抑制这些 RTK 的下游信号传导事件。根据AQ的类型和浓度以及所检查的细胞类型，这与抑制祖细胞分裂（在亚致死剂量下）以及在较高浓度下诱导祖细胞和/或少突胶质细胞死亡有关。目标 2 测试了以下假设：Fyn/c-Cbl 途径的激活在 A¿ 介导的少突胶质细胞谱系细胞分裂抑制和/或细胞死亡诱导中具有重要功能。目标 3 测试了这样的假设：防止 A¿ 毒性作用的抗氧化剂和营养因子抑制 A¿ 介导的氧化还原/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对阿尔茨海默病中枢神经系统造成损害的方式提供了新的见解。我们的研究确定了淀粉样蛋白破坏细胞功能的新分子途径，对这种疾病中髓鞘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毒性的新方法。