GLIA-MEDIATED BRAIN INJURY IN ALZHEIMER'S DISEASE

胶质细胞介导的阿尔茨海默病脑损伤

• 批准号: 6802057
• 负责人: Dana Giulian
• 金额: $ 11.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-07 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802057
• 关键词: Alzheimer's disease; NMDA receptors; amyloid proteins; animal tissue; biomarker; cerebrospinal fluid; chemical structure function; disease /disorder onset; electrospray ionization mass spectrometry; gas chromatography mass spectrometry; human tissue; laboratory rat; liquid chromatography mass spectrometry; microglia; neuritic plaques; neurotoxins; postmortem; tissue /cell culture

DESCRIPTION (adapted from applicant's abstract): Alzheimer's Disease (AD) is a degenerative disorder associated with senile plaques. Although loss of cortical neurons, decreased synaptic connections, and marked reactive microgliosis are prominent features of AD, the mechanisms to account for these histologic abnormalities remain uncertain. The investigators believe that AD plaques elicit local microglial reactivity and suggest that plaque-associated reactive microglia chronically release cytotoxic factors that contribute to the neuronal injury and synaptic loss resulting in AD dementia. They have identified and characterized neurotoxic activities, produced by microglia when brought into contact with isolated plaques. The same active principles can be extracted from autopsied AD brain. Isolated neurotoxic compounds, lipophilic amines, have been purified over 100,000 fold, show high potency and demonstrate in vivo effects in rat hippocampus. The investigators propose to elucidate the chemical structure of microglia-derived neurotoxins by mass spectrometric and biological studies. They will conduct studies to follow levels of neurotoxins in brain and cerebrospinal fluid. In addition, they will evaluate populations of neurons to determine patterns of vulnerability to microglia-derived neurotoxins. If successful, this proposed research will uncover fundamentally important events that regulate immune-mediated injury to AD brain. Elucidating neurotoxin structures will spur the development of new strategies to treat AD dementia.

描述（改编自申请人的摘要）：阿尔茨海默氏病（AD）是 与老年斑有关的退行性障碍。虽然是皮质的损失 神经元，突触连接降低以及明显的反应性小胶质细胞增多是 AD的突出特征，解释这些组织学的机制 异常仍然不确定。调查人员认为广告斑块 引起局部小胶质反应性，并提出与斑块相关的反应性 小胶质细胞长期释放有助于神经元的细胞毒性因子 损伤和突触损失导致AD痴呆。他们已经确定了 特征的神经毒性活性，被小胶质细胞产生时 与孤立的斑块接触。可以从相同的主动原理中提取 尸体大脑。孤立的神经毒性化合物，亲脂胺，已经是 纯化超过100,000倍，表现出高效力并在体内效应 在大鼠海马中。 研究人员建议阐明 通过质谱和生物学研究的小胶质细胞衍生的神经毒素。 他们将进行研究以跟随大脑中神经毒素的水平，并 脑脊液。此外，他们将评估神经元的种群 确定小胶质细胞衍生神经毒素的脆弱性模式。如果 成功，这项拟议的研究将发现根本重要的事件 调节免疫介导的AD脑损伤。阐明神经毒素 结构将促进治疗痴呆症的新策略的发展。