Downstream Regulators of Beta-Amyloid Induced Neuronal Death

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。不溶性A的沉积，以及缠结的形成，突触和神经元的丢失 S病的阿尔茨海默病的特征。最近在阿尔茨海默病和阿尔茨海默病中发现了更多可溶的A？寡聚物种 这些可能与突触丢失有关。虽然关于它们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是很重要的。研究表明，增加的A？ 诱导突触毒性，这是一个与AD认知功能下降相关的参数。我们工作中的证据 来自其他实验室的研究表明，聚集态和寡聚体Aβ可诱导培养的神经元和 亚致死浓度的A会导致初级神经元和脑片的突触形态发生变化。 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。 阿尔茨海默病患者脑组织中caspase-2及其下游靶标Bim增加。我们提出，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。我们提出的假设是，存在剂量依赖的激活不同的 A型半胱氨酸天冬氨酸酶导致突触重塑、突触丢失和神经元死亡。亚致死剂量的A？ 激活caspase-3；在这种情况下，caspase-3不执行死亡，但负责重塑突触 对A？应答的保护机制；Caspase-3的活性受IAP的调节。随着不断增加 暴露时间或增加A？水平，突触修剪变得过度，导致突触毒性 进而诱导营养因子的剥夺，导致进一步的突触丧失，最终激活 Caspase-2与神经元死亡。致死剂量激活caspase-2和caspase-3；caspase-2诱导Bim和 执行神经元，caspase-3活性被cIAP1抑制执行死亡。不同的复合体提供服务 以调节神经元中caspase-2的活性。Caspase-2的激活需要RAIDD；与RAIDD的PIDD复合体 以防止caspase-2被激活。我们将使用PRIMARY来检验这些假设 海马神经元培养和小鼠神经变性模型，具体目的如下：1. 确定半胱氨酸天冬氨酸氨基转移酶是如何调节A？诱导的突触丢失的。2：确定半胱氨酸酶是如何 受A？和TFD的调节和激活。3：确定caspase-2如何调节BIM的诱导 经过A？治疗后。

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.