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（由应用程序提供）：此“探索性”应用的目的是提供对淀粉样蛋白（A»）蛋白质的脆弱性的新型机械理解，以及A中断这些细胞功能在维持正常髓鞘中至关重要的途径的途径。我们最近发现了一种新型的调节途径，该途径在氧化变化和控制细胞信号传导之间提供了顺序连接。在这一途径中，通过细胞暴露于化学多样性的物质引起的具有氧化活性的化学生物引起的氧化状态的增加会导致Fyn激酶的激活。这导致C-CBL激活是FYN的靶标的E3泛素连接酶。 C-CBL的激活导致其靶蛋白的泛素化，其中包括受体酪氨酸激酶（RTK）的子集。由于它们与C-CBL的相互作用，这些RKT的降解得到了增强，从而抑制了下游信号传导。由于这种退化，抑制了ERK1/2和AKT等信号传导介质的下游激活。正如人们可以从这种作用中预测的那样，细胞分裂被抑制，细胞存活也可能受到损害。现在，我们建议检验以下假设：FYN/C-CBL途径的激活在淀粉样蛋白（a？）毒性中起重要作用。由于髓磷脂损伤在AD病理学中的重要性，实验提出了焦点对A肽对少突胶质细胞及其祖细胞的影响。此外，由于FYN/C-CBL假设还预测，暴露于促氧化剂刺激的浓度将抑制细胞分裂，我们将进一步测试以下假说：肽是少突肾细胞的细胞毒性，但也抑制了它们从中产生的祖细胞。如果此预测正确，则表明A两者都会损坏形成髓磷脂的细胞并抑制修复所需的细胞分裂。因此，这项研究提出了一种新的分子途径，该途径会影响细胞功能。先前的几项研究表明，FYN在AD的发病机理中起着重要作用。我们的研究将提供有关FYN激活可能破坏AD中细胞功能的机制的新见解。 AIM 1检验了以下假设：少突胶质细胞及其祖细胞暴露于A域引起氧化还原/FYN/C-CBL途径的激活，C-CBL靶标的RTK降解以及对这些RTKS下游信号事件的选择性抑制。这取决于A检测的类型和浓度以及所检查的细胞类型，祖细胞分裂的抑制（以余剂剂量）以及较高浓度的祖细胞和/或少突胶质细胞死亡的诱导。 AIM 2检验了以下假设：FYN/C -CBL途径的激活在降低细胞分裂的抑制和/或少突胶质细胞谱系中细胞死亡的诱导在功能上很重要。 AIM 3检验了以下假设：抗氧化剂和营养因子可以防止A抑制A介导的氧化还原/FYN/C-CBL途径的毒性作用，从而为AD中抗氧化剂的保护作用提供了新的潜在作用部位。 公共卫生相关性：这项研究提供了有关淀粉样蛋白在阿尔茨海默氏病中损害蛋白质损害的手段的新见解。我们的研究确定了一种新颖的分子途径，淀粉样蛋白破坏细胞功能，对这种疾病中髓鞘造成的广泛损害的发病机理的新见解，以及对抗氧化治疗可保护淀粉样蛋白影响的新理解。这项研究将有助于确定防止淀粉样蛋白毒性的新方法。