NEW RELATIONSHIP OF APOE TO NEURONAL VULNERABILITY IN AD

APOE 与 AD 神经元脆弱性的新关系

• 批准号: 6218639
• 负责人: DONALD E SCHMECHEL
• 金额: $ 22.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6218639
• 关键词: Alzheimer's disease; apolipoprotein E; apolipoproteins; gene expression; genetically modified animals; genotype; glia; hippocampus; human genetic material tag; human old age (65+); human tissue; immunocytochemistry; laboratory mouse; macroglobulins; neural degeneration; neuritic plaques; neuroanatomy; neurofibrillary tangles; neurons; partial seizure; pathologic process; postmortem; protein isoforms; receptor; receptor expression; temporal lobe /cortex

Alzheimer's disease (AD) is characterized by a devastating and progressive loss of memory and cognitive function. This decline is closely related to selective degeneration and death of hippocampal and neocortical neurons. Recently, the epsilon4 allele of the gene for apolipoprotein E (apoE, protein; APO, gene) has been recognized as a genetic susceptibility factor in late onset AD. The actual protein apoE is present in many of ht pathological lesions of AD. However, the relationship of apoE to the pathogenesis of cell injury and death in AD remains to be clarified. One possibility is that apoE has an isoform-specific, direct effect on intraneuronal metabolism. For this to be the case. (1) apoE must be present in neurons: (2) since neurons do not synthesize apoE. cells that synthesize the protein must be located near the neurons and apoE must have a way of getting into neurons: (3) there must be a clear set of conditions under which a neuron will take up apoE. In order to investigate these factors, we will carry out the following specific aims in human hippocampus and temporal cortex from controls. AD patients, and surgical specimens from temporal lobe epilepsy patients: (1) Characterize apoE-containing human cortical neurons to provide information for the hypothesis that apoE uptake by human cortical neurons is a normal neuronal response to remodelling and repair, but confers age- and APOE- isoform specific risk for AD; and (2) Characterize relationship of type and location of apoE-containing glial cells and neuronal expression of alpha2- macroglobulin receptor to neuronal apoE uptake to test the hypothesis that apoE uptake by human cortical neurons depends on expression of 'apoE'receptors and the presence of nearby glial cells secreting apoE. These experiments will be carried out using specific immunocytochemistry for apoE and other relevant markers and comparing this to traditional markers of AD pathology. Using the same methodology, we will also investigate as a third specific aim (3) immunolocalization of apoE and its receptors in transgenic rodents containing the three major APOE alleles - APE alleles - APE2, APOE3, and APOE4. These experiments should both further our understanding of which classes of neurons that are particularly vulnerable to AD pathology and elucidate the role apolipoprotein E may play in that vulnerability. This information will assist in the evaluation and development of treatments to protect neocortical and hippocampal neurons from the devastating effects of AD.

阿尔茨海默病 (AD) 的特点是具有破坏性和进行性 记忆和认知功能丧失。 这种下降与 海马和新皮质神经元的选择性变性和死亡。 最近，载脂蛋白 E 基因的 epsilon4 等位基因（apoE， 蛋白质; APO，基因）已被公认为遗传易感因素 在AD晚期。 实际的蛋白质 apoE 存在于许多 ht 中 AD的病理损害。 然而，apoE 与 AD 中细胞损伤和死亡的发病机制仍有待阐明。 一 可能性是 apoE 对同种型具有特异性的直接影响 神经元内代谢。 对于这种情况。 (1) apoE 必须是 存在于神经元中：(2)因为神经元不合成apoE。细胞 合成蛋白质必须位于神经元附近，apoE 必须具有 一种进入神经元的方法：（3）必须有一组清晰的 神经元吸收 apoE 的条件。 为了调查这些因素，我们将进行以下工作 对照中人类海马体和颞叶皮层的特定目标。 广告 患者和颞叶癫痫患者的手术标本：(1) 表征含有 apoE 的人类皮质神经元以提供信息 假设人类皮质神经元对 apoE 的摄取是正常的 神经元对重塑和修复的反应，但赋予年龄和 APOE- AD 亚型特定风险； (2) 表征类型和的关系 含有 apoE 的神经胶质细胞的位置和 alpha2- 的神经元表达 巨球蛋白受体对神经元 apoE 的摄取来检验以下假设： 人类皮质神经元对 apoE 的摄取取决于 “apoE”受体和附近分泌 apoE 的神经胶质细胞的存在。 这些实验将使用特定的免疫细胞化学进行 对于 apoE 和其他相关标记，并将其与传统的进行比较 AD 病理学的标志物。 使用相同的方法，我们还将 第三个具体目标是研究 (3) apoE 的免疫定位及其 转基因啮齿动物中含有三个主要 APOE 等位基因的受体 - APE 等位基因 - APE2、APOE3 和 APOE4。 这些实验应该进一步加深我们对哪些类别的理解 特别容易受到 AD 病理影响的神经元，并阐明了 载脂蛋白 E 可能在该脆弱性中发挥作用。 此信息 将协助评估和开发治疗方法以保护 新皮质和海马神经元免受 AD 的破坏性影响。