OXIDATIVE STRESS, CALCIUM, AND MITROCHONDRIAL DYSFUNCTION IN ALZHEIMER'S DISEASE

阿尔茨海默病中的氧化应激、钙和线粒体功能障碍

• 批准号: 7475681
• 负责人: D. Allan Butterfield
• 金额: $ 23.98万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7475681
• 关键词: 3-nitrotyrosine; 4 hydroxynonenal; Acids; Adult; Advanced Glycosylation End Products; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Model; Animals; Antioxidants; Apoptosis; Astrocytes; Behavioral; Biological Assay; Biological Markers; Brain; Brain region; Caenorhabditis elegans; Calcium; Cell Death Signaling Process; Cells; Cerebellum; Collaborations; Complex; Creatine Kinase; Data; Deposition; Development; Disease; Dose; Electrophysiology (science); Elevation; Embryo; End Point; Enzymes; Estrogens; Fluorescence; Free Radicals; Functional disorder; Gene Mutation; Genes; Glutamate-Ammonia Ligase; Glutathione; Goals; Homeostasis; Human; Immune; Impairment; In Vitro; Inflammation; Inflammatory; Inherited; Intervention; Intervention Studies; Investigation; Knock-in Mouse; Laboratories; Lead; Life; Link; Lipid Peroxidation; Measures; Memory; Microglia; Microscopy; Minocycline; Mitochondria; Modeling; Modification; Molecular; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neuroglia; Neurons; Nitrates; Oligodendroglia; Outcome Study; Oxidative Stress; Participant; Pathogenesis; Pathology; Pathway interactions; Persons; Prevention; Process; Production; Program Research Project Grants; Proteasome Inhibition; Protein Overexpression; Proteins; Proteomics; Rattus; Reactive Oxygen Species; Relative (related person); Reporting; Research; Rodent; Rodent Model; Role; Running; S-ethyl glutathione; Series; Signal Transduction; Source; Stimulus; Stress; Sulfhydryl Compounds; System; Testing; Therapeutic; Therapeutic Effect; Thinking; Thioctic Acid; Wild Type Mouse; Work; age related; aged; aging brain; base; cell type; cognitive function; cytochrome c; cytotoxicity; design; experience; familial Alzheimer disease; improved; in vivo; indexing; inhibitor/antagonist; insight; mature animal; mimetics; mind control; mitochondrial dysfunction; mouse model; multicatalytic endopeptidase complex; mutant; nitrate; normal aging; novel; oxidation; peptide A; presenilin-1; prevent; prototype; research study; response; rhod-2; success; xanthate D609

Aging, and age-related disorders such as Alzheimer's disease (AD), are associated with progressive decreases in cognitive function. Markers of inflammation are also well-documented in both aging and AD brains, but it is not known how inflammatory pathways are initiated, nor are the cell types involved in the inflammatory cascade identified. In addition to inflammation, calcium overload, oxidative stress, and proteasome inhibition are all thought to participate in age-related declines. New data from our laboratory suggests that these seemingly disparate phenomena may be linked; whereby changes in proteasome expression and activity in response to increased intracellular calcium and oxidative stress initiate inflammation in neurons. The focus of this proposal, therefore, is to test the hypothesis that oxidative stress- and calcium-induced alterations to the proteasome lead to inflammation in aging and AD brains. Studies will determine the effects of increasing doses of age- and AD-related stimuli on proteasome subunit expression, proteasome activity, and immune signaling in cultured neurons. The relationships between proteasome alterations, calcium homeostasis, inflammatory signaling, and cell death will be determined. Studies will also be carried out in cultured astrocytes, microglial cells, and oligodendrocytes to determine cell-type specific components of proteasome-dependent inflammation and cytotoxicity. Additionally, the role of preserved proteasome homeostasis and prevention of proteasome-dependent inflammation in the therapeutic effects of minocycline and estrogen will be tested in vitro and in vivo. Concurrently, this project will serve as a Core for the PPG, generating primary cultures of rat neurons and glial cells and providing quantitative assessments of inflammatory and proteasome homeostasis in long-term intervention studies. Completion of these studies will greatly increase our understanding of the role of the proteasome in the aging brain, and could aid in the development of novel therapies for brain aging by targeting inflammation.

衰老和与年龄有关的疾病，例如阿尔茨海默氏病（AD） 认知功能的逐步降低。炎症的标记也有充分的文献记录在衰老和广告大脑中，但尚不清楚炎症途径是如何启动的，也没有鉴定出炎症性级联反应的细胞类型。除炎症外，钙 人们认为过载，氧化应激和蛋白酶体抑制都参与年龄有关 下降。我们实验室的新数据表明，这些看似不同的现象可能是联系在一起的。蛋白酶体表达和活性随着细胞内钙和氧化应激的响应而变化会引起神经元的炎症。因此，该提案的重点是检验以下假设：氧化应激和钙诱导的蛋白酶体改变会导致衰老和AD大脑的炎症。研究将确定增加剂量的年龄和AD相关刺激对培养神经元中蛋白酶体亚基表达，蛋白酶体活性和免疫信号传导的影响。将确定蛋白酶体改变，钙稳态，炎症信号传导和细胞死亡之间的关系。研究还将在培养的星形胶质细胞，小胶质细胞和少突胶质细胞中进行，以确定蛋白酶体依赖性炎症和细胞毒性的细胞类型特异性成分。此外，将在体外和体内测试保留的蛋白酶体稳态和预防蛋白酶体依赖性炎症在米诺环素和雌激素的治疗​​作用中的作用。 同时，该项目将作为PPG的核心，产生老鼠的主要培养物 神经元和神经胶质细胞，并提供炎症和蛋白酶体的定量评估 长期干预研究中的稳态。这些研究的完成将大大提高我们对蛋白酶体在衰老大脑中的作用的理解，并可以通过靶向炎症来开发用于大脑衰老的新疗法。