CELLULAR PROCESSING OF APOE3 AND APOE4

APOE3 和 APOE4 的细胞处理

• 批准号: 3726238
• 负责人: MICHAEL P SHEETZ
• 金额: --
• 依托单位: DUKE UNIVERSITY
• 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/3726238
• 关键词: Alzheimer's disease; apolipoproteins; cell migration; cell motility; cellular pathology; endocytosis; fluorescent dye /probe; growth cones; immunocytochemistry; immunofluorescence technique; neural degeneration; neurogenesis; neuronal transport; neurons; protein isoforms; protein metabolism; receptor mediated endocytosis; spinal ganglion; tissue /cell culture; vesicle /vacuole; video microscopy

Recent genetic evidence has shown that the age of onset of Alzheimer's disease (AD) correlates inversely with the concentration of the apolipoprotein E (apoE) variant 4. How the single amino acid change from variant 3 to variant 4 leads to neurodegeneration and tangles is not understood. There are two obvious routes of action of apoE that could lead to neurodegeneration; either, apoE4 could be entering the cell cytoplasm through a transmembrane flip process in the endocytic pathway or it could be inducing a signal that results in the degenerative process. We propose to follow the paths of uptake of apoE3 and E4 in dorsal root ganglion (DRG) neurons as well as the responses that they stimulate to differentiate between the possible mechanisms. Our long-term interest in neuronal transport and processing has stimulated us to address the question of the biological differences between apoE3 and E4 and how they might affect neuronal and biochemical differences between the two forms have been observed and we will determine if and how those differences can result in changes in cellular motility. Using specifically tagged apoEs and/or specific antibodies, we will follow the fate of the apoEs and the stimuli that they elicit. We will characterize the changes in axon extension and branching caused by apoE4 and will analyze its effect on microtubule- dependent motility. These studies will identify the cellular pathway of apoE processing and the bases of its effects on motility.

最近的遗传学证据表明，老年痴呆症的发病年龄 疾病（AD）与药物浓度呈负相关。 载脂蛋白E（apoE）变体4。 单个氨基酸是如何从 变体3到变体4导致神经变性，而缠结不是 明白 apoE有两种明显的作用途径， apoE 4也可以进入细胞质 通过内吞途径中的跨膜翻转过程， 会引发导致退化过程的信号 我们提出 追踪背根神经节（DRG）摄取apoE 3和E4的途径 神经元以及它们刺激分化的反应 可能的机制之间。 我们对神经元的长期兴趣 运输和加工促使我们解决 apoE 3和E4之间的生物学差异以及它们如何影响 这两种形式之间的神经元和生物化学差异已经被 观察，我们将确定这些差异是否以及如何导致 细胞运动性的变化。 使用特异性标记的apoE和/或 特异性抗体，我们将跟踪apoE和刺激物的命运， 它们所引发的。 我们将描述轴突延伸的变化， 支化引起的apoE 4，并将分析其对微管的影响， 依赖性运动 这些研究将确定的细胞途径， apoE的加工及其对运动影响的基础。