Downstream Regulators of Beta-Amyloid Induced Neuronal Death

β-淀粉样蛋白诱导的神经元死亡的下游调节因子

• 批准号: 7652644
• 负责人: CAROL M TROY
• 金额: $ 35.15万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652644
• 关键词: 3xTg-AD mouse; Amyloid; Amyloid beta-Protein; Apoptosis; BCL2L11 gene; Biochemical; Biological Models; Brain; Caspase; Cell Cycle; Cell Death; Cessation of life; Chromosome Pairing; Complex; Deposition; Disease; Dose; Electrons; Family member; Hippocampus (Brain); Hour; Impaired cognition; Laboratories; Location; MAPK8 gene; Mediating; Microscopic; Molecular; Morphology; Nerve Degeneration; Neurons; Pathway interactions; Positioning Attribute; Process; Proteomics; Regulation; Role; Slice; Structure; Synapses; Synaptic plasticity; Syndrome; Time; Work; caspase-2; caspase-3; comparative; deprivation; mouse Ts65Dn; mouse model; neurofibrillary tangle formation; neuron loss; prevent; response

Our overall aim is to determine the molecular mechanisms of ¿-amyloid (A¿)-induced synaptic loss and neuronal death. Deposition of insoluble A¿, together with tangle formation, loss of synapses and neurons, are hallmarks of Alzheimer¿s disease. More recently soluble A¿ oligomeric species have been found in AD and these may correlate with synaptic loss. While the debate continues about the role of each of these in the disease it is important to develop model systems where these processes can be studied. Studies show that increased A¿ induces synaptotoxicity, a parameter which correlates with cognitive decline in AD. Evidence from our work and from other laboratories shows that aggregated and oligomeric A¿ induce apoptosis in cultured neurons and that sublethal concentrations of A¿ induce changes in synapse morphology in primary neurons and brain slices. Our work shows that A¿ induces activation of caspase-2 and -3 but that only caspase-2 executes death. Caspase-2 and its downstream target Bim are increased in AD brains. We are proposing that, in neurons exposed to A¿, the main function of caspase-3 is the regulation of synaptic plasticity, not the execution of cell death; caspase-2 executes death. We propose the hypothesis that there is dose-dependent activation of different caspases by A¿ leading to synaptic remodeling, synaptic loss and neuronal death. Sublethal doses of A¿ activate caspase-3; caspase-3 in this setting does not execute death but is responsible for remodeling synapses as a protective mechanism in response to A¿; the activity of caspase-3 is modulated by IAPs. With increasing time of exposure or increasing levels of A¿, synapse pruning becomes excessive, leading to synaptotoxicity which in turn induces trophic factor deprivation leading to further synaptic loss and eventually to activation of caspase-2 and neuronal death. Lethal doses of A¿ activate caspase-2 and caspase-3; caspase-2 induces Bim and executes the neuron, caspase-3 activity is inhibited from executing death by cIAP1. Different complexes serve to regulate caspase-2 activity in neurons. Caspase-2 activation requires RAIDD; PIDD complexes with RAIDD in healthy neurons to prevent caspase-2 activation. We will examine these hypotheses using primary hippocampal neuron cultures and mouse models of neurodegeneration, with the following specific aims: 1. To determine how caspases regulate synaptic loss induced by A¿. 2: To determine how caspases are regulated and activated by A¿ and TFD. 3: To determine how caspase-2 regulates the induction of Bim after A¿ treatment.

我们的总体目标是确定 ¿-淀粉样蛋白 (A¿) 诱导的突触损失和 神经元死亡。不溶性 A 的沉积，以及缠结的形成、突触和神经元的损失， 阿尔茨海默病的特征。最近在 AD 和 这些可能与突触损失有关。虽然关于这些因素在疾病中的作用的争论仍在继续 开发可以研究这些过程的模型系统非常重要。研究表明，增加 A¿ 诱导突触毒性，这是与 AD 认知能力下降相关的参数。我们工作的证据 来自其他实验室的研究表明，聚集的和寡聚的 A¿ 会诱导培养的神经元细胞凋亡，并且 亚致死浓度的 A¿ 会引起初级神经元和脑切片中突触形态的变化。 我们的工作表明，A¿ 诱导 caspase-2 和 -3 的激活，但只有 caspase-2 执行死亡。 AD 大脑中 Caspase-2 及其下游靶标 Bim 增加。我们建议，在神经元中 暴露于A¿时，caspase-3的主要功能是调节突触可塑性，而不是细胞的执行 死亡; caspase-2 执行死亡。我们提出这样的假设：不同的激活作用存在剂量依赖性。 A¿ 的半胱天冬酶导致突触重塑、突触损失和神经元死亡。 A的亚致死剂量 激活 caspase-3； caspase-3 在这种情况下不会执行死亡，但负责将突触重塑为 响应 A¿ 的保护机制； caspase-3 的活性受 IAP 调节。随着增加 暴露时间或 A 水平增加，突触修剪变得过度，导致突触毒性 这反过来又导致营养因子剥夺，导致进一步的突触损失，并最终激活 caspase-2 和神经元死亡。致死剂量的 A¿ 会激活 caspase-2 和 caspase-3； caspase-2 诱导 Bim 和 执行神经元时，Caspase-3 活性被 cIAP1 抑制以执行死亡。不同的综合体服务 调节神经元中的 caspase-2 活性。 Caspase-2激活需要RAIDD； PIDD 与 RAIDD 复合体 在健康的神经元中防止 caspase-2 激活。我们将使用主要的方法来检验这些假设 海马神经元培养物和神经变性小鼠模型，具有以下具体目标： 1. 确定半胱天冬酶如何调节 A¿ 诱导的突触损失。 2：确定半胱天冬酶的性质 由 A¿ 和 TFD 调节和激活。 3: 确定 caspase-2 如何调节 Bim 的诱导 A¿处理后。