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: 7895609
• 负责人: CAROL M TROY
• 金额: $ 45.23万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895609
• 关键词: 3xTg-AD mouse; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Apoptosis; BCL2L11 gene; Biochemical; Biological Models; Brain; Caspase; Cell Cycle; Cell Death; Cessation of life; Complex; Deposition; Disease; Dose; Down Syndrome; 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; Time; Vertebral column; 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, and caspase-3 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 if caspase-3 and IAPs mediate spine changes induced by A_. 2. 2: To determine how caspase-2 is regulated and activated by A_ and TFD. 3: To determine how caspase-2 induces of Bim expression.

我们的总体目标是确定 _-淀粉样蛋白 (A_) 诱导的突触丢失和神经元死亡的分子机制。不溶性 A_ 的沉积，以及缠结的形成、突触和神经元的丧失，是阿尔茨海默病的标志。最近在 AD 中发现了可溶性 A_ 寡聚物质，这些物质可能与突触损失有关。虽然关于这些过程在疾病中的作用的争论仍在继续，但开发可以研究这些过程的模型系统非常重要。研究表明，A_ 增加会诱发突触毒性，这是与 AD 认知能力下降相关的参数。我们的工作和其他实验室的证据表明，聚集和寡聚的 A_ 会诱导培养的神经元细胞凋亡，亚致死浓度的 A_ 会诱导原代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。 Caspase-2 及其下游靶标 Bim 和 caspase-3 在 AD 大脑中增加。我们提出，在暴露于A_的神经元中，caspase-3的主要功能是调节突触可塑性，而不是执行细胞死亡； caspase-2 执行死亡。我们提出这样的假设：A_ 对不同的半胱天冬酶存在剂量依赖性激活，导致突触重塑、突触损失和神经元死亡。亚致死剂量的A_激活caspase-3； caspase-3 在这种情况下并不执行死亡，而是负责重塑突触作为响应 A_ 的保护机制； caspase-3 的活性受 IAP 调节。随着暴露时间的增加或 A_ 水平的增加，突触修剪变得过度，导致突触毒性，进而诱导营养因子剥夺，导致进一步的突触损失，最终导致 caspase-2 激活和神经元死亡。致死剂量的A_激活caspase-2和caspase-3； caspase-2诱导Bim并执行神经元，caspase-3活性被cIAP1抑制而执行死亡。不同的复合物可调节神经元中的 caspase-2 活性。 Caspase-2激活需要RAIDD； PIDD 与健康神经元中的 RAIDD 复合以防止 caspase-2 激活。我们将使用原代海马神经元培养物和神经变性小鼠模型来检验这些假设，具体目标如下： 1. 确定 caspase-3 和 IAP 是否介导 A_ 诱导的脊柱变化。 2. 2：确定A_和TFD如何调节和激活caspase-2。图3：确定caspase-2如何诱导Bim表达。

项目成果

Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection.

• DOI: 10.1186/1750-1326-7-60
• 发表时间: 2012-12-10
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Tamayev R;Akpan N;Arancio O;Troy CM;D'Adamio L
• 通讯作者: D'Adamio L

Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory.

• DOI: 10.1002/ana.22313
• 发表时间: 2011-05
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Puzzo, Daniela;Privitera, Lucia;Fa, Mauro;Staniszewski, Agnieszka;Hashimoto, Gakuji;Aziz, Fahad;Sakurai, Mikako;Ribe, Elena M.;Troy, Carol M.;Mercken, Marc;Jung, Sonia S.;Palmeri, Agostino;Arancio, Ottavio
• 通讯作者: Arancio, Ottavio