Role of PS1 in regulation of adult neurogenesis in intact and Alzheimer's brain

PS1 在完整大脑和阿尔茨海默病大脑中成人神经发生的调节中的作用

• 批准号: 8234977
• 负责人: Orly Lazarov
• 金额: $ 30.04万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234977
• 关键词: Ablation; Address; Adult; Affect; Aging; Alzheimer' s Disease; Area; Aspartic Endopeptidases; Astrocytes; Behavioral; Biochemical; Biological Assay; Brain; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Characteristics; Cognitive; Deterioration; Generations; Genes; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Hippocampus (Brain); Human; Human Development; Injection of therapeutic agent; Investigation; Knock-out; Learning; Lentivirus Vector; Link; Memory; Memory Loss; Memory impairment; Molecular; Mus; Mutation; Neuroglia; Neurons; Pathology; Pathway interactions; Patients; Play; Population; Preparation; Process; Prosencephalon; Proteins; RNA Interference; Regulation; Role; Series; Signal Pathway; Signal Transduction; Small Interfering RNA; Smell Perception; Stem cells; Subfamily lentivirinae; System; Tetracyclines; Therapeutic; Trans-Activators; Transgenic Mice; Variant; Viral Vector; adult neurogenesis; base; cell motility; cell type; cellular transduction; dentate gyrus; familial Alzheimer disease; insight; knock-down; memory process; migration; mutant; nerve stem cell; nestin protein; neural circuit; neurogenesis; novel; olfactory bulb; presenilin-1; prevent; promoter; research study; secretase; self-renewal; subventricular zone; transgene expression

Patients affected with Alzheimer's disease suffer from severe neuronal damage, manifested by progressive memory loss and cognitive deterioration. Alzheimer's patients, who are currently untreatable, may benefit from the endogenous de novo generation of neurons, if we are able to understand the mechanisms that regulate neurogenesis, and how to manipulate them. Presenilin-1 (PS1) is a multi-pass protein that plays a major role in the aspartyl protease ¿-secretase. Mutations in the gene encoding PS1 cause Familial Alzheimer's disease (FAD). Recent evidence suggests that PS1 plays a role in adult neurogenesis. To gain an insight into the role of PS1 in neurogenesis, a process that takes place in discrete areas of the adult brain, we developed a lentiviral vector system that expresses small interfering RNAs (siRNA) for PS1 targeting, and green fluorescent protein for the tracking of transduced cells. We show that stereotaxic injection of these lentiviral vectors into neurogenic areas in the adult brain dramatically reduces neural stem cell proliferation and induces astrocyte differentiation. Based on our intriguing preliminary results we hypothesis that PS1 plays a major role in neural stem cell proliferation and cell fate determination in the adult brain. In Specific Aim 1 we propose to determine the role of PS1 in regulation of neural stem cell proliferation, migration and cell fate determination by examining the effect of PS1 silencing on neural stem cells in the adult brain. In Specific Aim 2 we propose to define the role of PS1 in regulation of the neurogenic niche and of intrinsic pathways in neural stem cells. This will be achieved by expression of siRNA for PS1 silencing in a cell type-specific manner, in nestin-expressing neural stem cells and glial fibrillary acidic protein-expressing astrocytes. In Specific Aim 3 we propose to determine the role of PS1 in learning and memory in the adult brain. Using behavioral analysis, the effect of PS1 silencing in neural stem cells in neurogenic areas on learning and memory processes will be examined. In Specific Aim 4 we propose to determine the effect of FAD-linked mutant PS1 on adult neurogenesis by the generation of transgenic mice that will express FAD-linked PS1 variants in neural stem cells exclusively in the adult brain. This study proposes powerful approaches for the determination of the role of PS1 in neurogenesis and of the effect of Alzheimer's pathology on this process. These studies may have far-reaching therapeutic implications in the aging and Alzheimer's brain.

患有阿尔茨海默病的患者遭受严重的神经元损伤，表现为进行性神经元损伤。 记忆力丧失和认知能力衰退目前无法治愈的阿尔茨海默病患者可能会受益于 内源性神经元的新生，如果我们能够理解调节神经元的机制， 神经发生以及如何操纵它们。早老素-1（PS1）是一种多通道蛋白，在细胞凋亡中起主要作用。 乙酰基蛋白酶分泌酶PS1基因突变导致家族性阿尔茨海默病 （FAD）。最近的证据表明，PS1在成人神经发生中起作用。为了深入了解 PS1在神经发生中的作用，这是一个发生在成人大脑离散区域的过程，我们开发了一个 慢病毒载体系统，其表达用于PS1靶向的小干扰RNA（siRNA），和绿色荧光 用于追踪转导细胞的蛋白质。我们表明，立体定向注射这些慢病毒载体， 成年人大脑中的神经源性区域显著减少神经干细胞增殖并诱导星形胶质细胞 分化基于我们有趣的初步结果，我们假设PS1在神经细胞中起着重要作用。 干细胞增殖和细胞命运的决定。在具体目标1中，我们建议确定 通过检测PS1在神经干细胞增殖、迁移和细胞命运决定中作用 PS1沉默对成年脑中神经干细胞的影响。在具体目标2中，我们建议定义 PS1在调节神经源性小生境和神经干细胞内在通路中的作用。这将是 通过以细胞类型特异性的方式表达用于PS1沉默的siRNA，在表达巢蛋白的神经细胞中， 干细胞和表达胶质纤维酸性蛋白的星形胶质细胞。在具体目标3中，我们建议确定 PS1在成人大脑学习和记忆中的作用。使用行为分析，PS1沉默的影响 在神经干细胞的神经原性领域的学习和记忆过程将被检查。具体目标 4.我们建议通过产生FAD连锁突变体PS1来确定其对成年神经发生的影响。 转基因小鼠，将表达FAD连锁PS1变异体的神经干细胞专门在成年大脑。 这项研究为确定PS1在神经发生中的作用以及PS1在神经发生中的作用提供了强有力的方法。 老年痴呆症病理学对这一过程的影响。这些研究可能具有深远的治疗意义 在老年痴呆症的大脑中。