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）：这个“探索性”申请的目标是提供对淀粉样蛋白（a¿）易感性的新的机制理解，以及a¿破坏维持正常髓鞘形成的关键细胞功能的途径。我们最近发现了一种新的调控途径，它提供了氧化变化和细胞信号控制之间的顺序联系。在这一途径中，由于细胞暴露于具有促氧化活性的化学多样性物质中，导致氧化状态的增加，导致Fyn激酶的激活。这导致c-Cbl的激活，这是一种E3泛素连接酶，是Fyn的靶标。c-Cbl的激活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，导致下游信号的抑制。由于这种降解，下游信号介质如Erk1/2和Akt的激活被抑制。正如人们从这种效应所预测的那样，细胞分裂受到抑制，细胞存活也可能受到损害。我们现在提出验证Fyn/c-Cbl通路的激活在淀粉样蛋白（A¿）毒性中起重要作用的假设。由于髓磷脂损伤在阿尔茨海默病病理中的重要性，实验将重点关注A¿肽对少突胶质细胞及其祖细胞的影响。此外，由于Fyn/c- Cbl假设也预测暴露于亚致死浓度的促氧化刺激会抑制细胞分裂，我们将进一步验证A¿肽对少突胶质细胞具有细胞毒性，但也抑制产生它们的祖细胞分裂的假设。如果这一预测是正确的，这将表明A¿既损害髓磷脂形成细胞，又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，通过该途径a¿影响细胞功能。先前的一些研究表明Fyn在AD的发病机制中起重要作用。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。目的1验证了少突胶质细胞及其祖细胞暴露于A¿导致氧化还原/Fyn/c-Cbl途径的激活，c-Cbl靶点rtk的降解以及这些rtk的下游信号事件的选择性抑制的假设。根据A¿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）和在较高浓度下诱导祖细胞和/或少突胶质细胞死亡有关。目的2验证了Fyn/c-Cbl通路的激活在A¿介导的细胞分裂抑制和/或诱导少突胶质细胞谱系的细胞死亡中具有重要功能的假设。目的3验证了一种假设，即抗氧化剂和营养因子可以抑制A¿介导的氧化还原/Fyn/c-Cbl通路的激活，从而为抗氧化剂在AD中的保护作用提供了一种新的潜在作用位点。