COBRE: UND: TNF-ALPHA/GLUTAMATE INDUCED CELL DEATH IN ALZHEIMER'S DISEASE

COBRE：UND：TNF-α/谷氨酸诱导的阿尔茨海默病细胞死亡

• 批准号: 7381899
• 负责人: Colin K Combs
• 金额: $ 18.09万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381899
• 关键词: COBRE; UND; TNF; ALPHA; GLUTAMATE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Microglial-dependent inflammation is critical for neurodegenerative conditions ranging from Alzheimer¿s disease (AD) to multiple sclerosis and Parkinson¿s disease. Therefore,toxic microglial proinflammatory products as well as their specific mechanisms of neuronal toxicity are likely common to numerous pathological situations. Identifying the nature of these toxins as well as their modes of action will provide molecular targets for preventing the inflammatory changes in numerous neurodegenerative conditions. Although abundant reactive microglia are found associated with beta-amyloid plaques in AD brains, their precise contribution to cell loss remains speculative. In vitro, fibrils stimulate microglia to secrete neurotoxic products suggesting that microglial inflammation directly contributes to cell death in AD. Preliminary evidence demonstrates that amyloid beta fibrils stimulate cultured mouse microglia to secrete the excitatory neurotransmitter, glutamate, and the pro-inflammatory cytokine, TNF alpha. These proinflammatory secretions directly induce death of mouse cortical neuron cultures in an oxidative damage-dependent fashion requiring increased neuronal expression of inducible nitric oxide synthase and subsequent peroxynitrite production. Neuron death results from coincident stimulation of the TNF receptor (p55) and NMDA receptors, as neither factor, alone, is sufficient to initiate cell death. Accordingly, we will test the hypothesis that AD brains provide the appropriate microglial-mediated inflammatory environment for TNF alpha and glutamate to synergistically stimulate TNF alpha and glutamate receptor signaling pathways and cause cell death. The following specific aims will address this hypothesis: 1) Determine whether necrotic or apoptotic cell death is induced by synergistic stimulation of neuronal cortical cultures with TNF alpha and the glutamate receptor agonist, NMDA. 2) Identify the mechanisms of nontoxic TNF alpha alone and nontoxic NMDA alone-mediated signaling responses in neurons. 3) Determine the mechanisms of the synergistic TNF alpha + NMDA mediated signaling cross-talk responsible for oxidative damage-dependent neuron death.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。小胶质细胞依赖性炎症对从阿尔茨海默病、S病(AD)到多发性硬化症和帕金森S病等神经退行性疾病至关重要。因此，有毒的小胶质细胞前炎症产物及其神经元毒性的具体机制可能在许多病理情况下都是常见的。识别这些毒素的性质以及它们的作用模式将为预防许多神经退行性疾病的炎性变化提供分子靶点。虽然在AD大脑中发现了丰富的反应性小胶质细胞与β-淀粉样斑块有关，但它们对细胞丢失的确切贡献仍然是推测的。在体外，纤维刺激小胶质细胞分泌神经毒性产物，表明小胶质细胞炎症直接导致AD细胞死亡。初步证据表明，淀粉样β纤维刺激培养的小鼠小胶质细胞分泌兴奋性神经递质谷氨酸和促炎细胞因子TNFα。这些促炎分泌物以氧化损伤依赖的方式直接诱导培养的小鼠皮质神经元死亡，需要增加神经元诱导型一氧化氮合酶的表达，并随后产生过氧亚硝酸盐。神经元死亡是由于同时刺激肿瘤坏死因子受体(P55)和NMDA受体，因为这两个因素本身都不足以启动细胞死亡。因此，我们将验证这一假设，即AD大脑为肿瘤坏死因子α和谷氨酸提供适当的小胶质细胞介导的炎症环境，协同刺激肿瘤坏死因子α和谷氨酸受体信号通路，导致细胞死亡。以下具体目标将解决这一假说：1)确定神经元皮质培养与肿瘤坏死因子α和谷氨酸受体激动剂NMDA协同刺激是否诱导坏死性或凋亡性细胞死亡。2)明确无毒的肿瘤坏死因子α和无毒的NMDA单独介导的神经元信号反应的机制。3)确定协同的肿瘤坏死因子α+NMDA介导的信号串扰导致氧化损伤依赖性神经元死亡的机制。