The Subcellular Neuropathology of Alzheimer's Disease

阿尔茨海默病的亚细胞神经病理学

• 批准号: 6702603
• 负责人: GUNNAR K GOURAS
• 金额: $ 24.15万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702603
• 关键词: Alzheimer' s disease; aging; amyloid proteins; enzyme linked immunosorbent assay; fluorescence microscopy; genetically modified animals; immunocytochemistry; immunoelectron microscopy; laboratory mouse; neurofibrillary tangles; neurons; neuropathology; pathologic process; peptides; synapses; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by the accumulation of 13-amyloid peptides (AI3) in the brain. AI3 is generated intracellularly by the regulated cleavage of the 13-amyloid precursor protein (APP). We propose to study the subcellular site(s) where AI3 peptides localize and accumulate with aging, and how this may initiate AD plaque pathology, in transgenic mice carrying familial AD (FAD) mutations. We have recently found that Al342 localizes to multivesicular bodies (MVBs) especially within AD-vulnerable pyramidal neurons in both normal and AD transgenic mouse, and in rat and human brain, but not in APP knockout mouse brain. Since our previous immunohistochemical studies suggested that intraneuronal AI342 accumulation occurs with Alzheimer's disease, we propose to study brain tissue from AD transgenic mice in the process of developing AI3 plaques for evidence of changes in the amount and subcellular distribution of AI340 and AI342 and various APP fragments, also in distal neuronal processes and synapses, using immuno-electron microscopy and subcellular fractionation methods. We plan to assess the amount and subcellular distribution of AI3 peptides at various ages prior and during the time when plaque deposition is known to occur in the specific transgenic AD mice under study; Tg2576 mice expressing the FAD Swedish 670/671 mutant human APP generally develop AI3 plaques at approximately 11 to 13 months of age. In addition, we propose to study the neurobiology and regulation of this MVB-associated pool of AI3 in cultured primary neurons, and to investigate for changes in neuronal MVBs with aging and AD pathogenesis. We hypothesize that accumulation, and potentially aggregation, of AI342 with aging on the outer membrane of MVBs may interfere with the normal transport of vital cargo molecules within neuronal processes. A better understanding of the cellular and molecular events occurring within neurons of the brain involved in AD pathogenesis may be important for the development of more effective molecular based treatment strategies for Alzheimer's disease.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by the accumulation of 13-amyloid peptides (AI3) in the brain. AI3 is generated intracellularly by the regulated cleavage of the 13-amyloid precursor protein (APP).我们建议在携带家族性 AD (FAD) 突变的转基因小鼠中研究 AI3 肽随着衰老而定位和积累的亚细胞位点，以及这如何引发 AD 斑块病理学。我们最近发现，Al342 定位于多泡体 (MVB)，尤其是在正常和 AD 转基因小鼠、大鼠和人脑中 AD 易受影响的锥体神经元内，但不在 APP 敲除小鼠脑中。由于我们之前的免疫组织化学研究表明神经元内 AI342 积累与阿尔茨海默氏病有关，因此我们建议研究 AD 转基因小鼠在形成 AI3 斑块的过程中的脑组织，以获取 AI340 和 AI342 以及各种 APP 片段的数量和亚细胞分布变化的证据，以及在远端神经元过程和突触中，使用 immuno-electron microscopy and subcellular fractionation methods.我们计划评估所研究的特定转基因 AD 小鼠中已知发生斑块沉积之前和期间不同年龄的 AI3 肽的数量和亚细胞分布； Tg2576 mice expressing the FAD Swedish 670/671 mutant human APP generally develop AI3 plaques at approximately 11 to 13 months of age.此外，我们建议研究培养的原代神经元中与 MVB 相关的 AI3 池的神经生物学和调节，并研究神经元 MVB 随衰老和 AD 发病机制的变化。我们假设，随着 MVB 外膜老化，AI342 的积累和潜在聚集可能会干扰神经元过程中重要货物分子的正常运输。更好地了解参与 AD 发病机制的大脑神经元内发生的细胞和分子事件可能对于开发更有效的基于分子的阿尔茨海默病治疗策略非常重要。