Protective Role of Astrocytic Nrf2 in AD Mouse Models and Human AD Brain

星形胶质细胞 Nrf2 在 AD 小鼠模型和人类 AD 脑中的保护作用

• 批准号: 8677362
• 负责人: Jeffrey A Johnson
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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/8677362
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Adaptor Signaling Protein; Affect; Age; Age-Months; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Astrocytes; Autophagocytosis; Autophagosome; Brain; C-terminal; Cell Nucleus; Complex; Data; Dissection; Etiology; Family; Foundations; Functional disorder; Generations; Genes; Glial Fibrillary Acidic Protein; Harvest; Hippocampus (Brain); Human; In Vitro; Individual; Inflammation; Laboratories; Longevity; Lysosomes; Mediating; Mus; Mutant Strains Mice; Mutation; NF-E2-related factor 2; Neurites; Neuritis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Onset of illness; Oxidative Stress; Pathogenesis; Pathology; Patients; Phase; Phosphorylation; Production; Protein Fragment; Proteins; Proteolysis; Publications; Publishing; Research; Role; Side; Staging; Staining method; Stains; System; Tissues; Ubiquitin; Ubiquitination; Vacuole; Wisconsin; Work; abstracting; alpha synuclein; amyloid precursor protein processing; base; cohort; density; early onset; familial Alzheimer disease; human FRAP1 protein; hyperphosphorylated tau; in vivo; mitochondrial dysfunction; mouse model; multicatalytic endopeptidase complex; mutant; novel; overexpression; protein aggregate; protein degradation; secretase; transcription factor; ubiquitin-protein ligase

PROJECT 1 - PROJECT SUMMARY / ABSTRACT Alzheimer's disease (AD), an age associated neurodegenerative disorder, is pathologically characterized by plaques consisting of aggregated beta-amyloid (Aβ) and intracellular neurofibrillary tangles (NFT) formed by hyperphosphorylated tau. Aβ is formed by the sequential action of β and γ secretase on the C-terminal side of amyloid precursor protein (APP). Oxidative stress has been implicated in human AD patients and several studies have shown Aβ-mediated oxidative stress to be central to the AD pathogenesis and progression. In addition to, or associated with oxidative stress, a reduction/dysfunction of autophagy is observed in AD. Autophagic vacuoles (AVs) that are rarely observed in neurons of healthy individuals are found to accumulate in the dystrophic and less affected neuritis in AD. Indeed, autophagy is hypothesized to be a major mechanism mediating APP turnover normally and generation of intracellular Aβ when dysfunctional. NF-E2- related factor 2 (Nrf2) has been implicated to be involved, not only in mitigating oxidative stress, but also an important factor in regulating and responding directly and indirectly to the changes in autophagy in vivo and in vitro. There is little work examining the role of Nrf2 in APP processing/turnover and Aβ production/degradation in AD with no information existing in the animal models of AD or human AD tissue. Recently, data from our laboratory found that overexpression of Nrf2 in astrocytes (GFAP-Nrf2) dramatically delays autophagic dysfunction in neurons of alpha synuclein A53T mice. This correlated with a highly significant delay in disease onset and extension of lifespan. Initial crosses of our GFAP-Nrf2 mice with APP/PS1 mice demonstrate a reduced plaque density and a dramatic reduction in intracellular APP or cleavage products. Thus, the specific aims of this proposal are: Aim 1. To determine the effect of astrocytic Nrf2 overexpression on APP processing/turnover and Aβ production/degradation in APP/PS1 mice. Aim 2. To elucidate the mechanism involved in astrocytic Nrf2-mediated changes in APP processing/turnover and Aβ production/degradation in astrocyte-neuron cultures derived from APP/PS1 mice. Aim 3. To determine changes in astrocytic Nrf2 activation in possible/early and definitive/late stage human AD brain. Completion of the proposed studies will solidify the significance of astrocytic Nrf2 activation as a modulator of AD pathology.

项目 1 - 项目摘要/摘要 阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其病理特征是 由聚集的β-淀粉样蛋白（Aβ）和细胞内神经原纤维缠结（NFT）组成的斑块 过度磷酸化的 tau 蛋白是由 β 和 γ 分泌酶在 C 端侧的连续作用形成的。 淀粉样前体蛋白 (APP) 与人类 AD 患者和一些患者有关。 研究表明 Aβ 介导的氧化应激是 AD 发病机制和进展的核心。 除了氧化应激之外，或与氧化应激相关，在 AD 中还观察到自噬减少/功能障碍。 在健康个体的神经元中很少观察到的自噬液泡（AV）被发现会积累 事实上，在 AD 的营养不良和受影响较小的神经炎中，自噬重新成为主要因素。 当 NF-E2- 功能失调时，介导 APP 正常更新和细胞内 Aβ 生成的机制。 相关因子 2 (Nrf2) 不仅参与减轻氧化应激，还参与 直接和间接调节和响应体内外自噬变化的重要因素 很少有研究研究 Nrf2 在 APP 加工/周转和 Aβ 产生/降解中的作用。 最近，我们的数据显示，AD 动物模型或人类 AD 组织中不存在任何信息。 实验室发现星形胶质细胞中 Nrf2 的过度表达 (GFAP-Nrf2) 会显着延迟自噬 α突触核蛋白A53T小鼠的神经元功能障碍这与疾病的显着延迟相关。 我们的 GFAP-Nrf2 小鼠与 APP/PS1 小鼠的初始杂交表明了寿命的开始和延长。 斑块密度降低，细胞内 APP 或裂解产物显着减少。 该提案的目标是： 目标 1. 确定星形胶质细胞 Nrf2 过度表达对 APP 的影响 APP/PS1 小鼠中的加工/周转和 Aβ 产生/降解 目标 2. 阐明其机制。 参与星形胶质细胞 Nrf2 介导的 APP 加工/周转和 Aβ 产生/降解的变化 源自 APP/PS1 小鼠的星形胶质细胞-神经元培养物 目标 3. 确定星形胶质细胞 Nrf2 的变化。 完成拟议的研究将激活可能/早期和最终/晚期的人类 AD 大脑。 巩固了星形胶质细胞 Nrf2 激活作为 AD 病理调节剂的重要性。