AAV VECTORS FOR ALZHEIMER'S DISEASE MODELING AND THERAPY

用于阿尔茨海默病建模和治疗的 AAV 载体

• 批准号: 6885142
• 负责人: Michael A King
• 金额: $ 12.91万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885142
• 关键词: Alzheimer' s disease; adeno associated virus group; amyloid proteins; disease /disorder etiology; disease /disorder model; disease /disorder onset; enzyme induction /repression; gene therapy; genetically modified animals; human genetic material tag; laboratory mouse; model design /development; molecular pathology; nerve growth factors; neurofibrillary tangles; neurotrophic factors; pathologic process; phosphoprotein phosphatase; phosphorylation; tau proteins; transfection /expression vector

We have used AAV vectors to generate, in rodents, phenomena that are associated with AIzheimer's disease (AD), and to counteract aspects of AD pathology. Neurofibrillary tangles (NFT) develop within weeks of surgical injection of an AAV vector carrying a human mutation in the gene encoding the microtubule-associated protein tau. Memory deficits were found a year after injection of a vector carrying familial AD mutations in amyioid precursor protein. Basal forebrain choiinergic neurons that are critical for memory, and which die in AD, have been protected against age- and injury-related loss of function by AAV vectors transducing the expression of nerve growth factor. We now propose to use this gene transfer technology to test in Aim 1 whether inibition of protein phosphatase 2A will result in dysfunction and pathology of tau in vivo. The activity of this enzyme has been found to be reduced in AD. Aim 2 will test whether overexpression of neuronal thread protein, found to be selectively and substantially elevated in AD, will induce any AD-reiated anatomical, behavioral, or biochemical pathology. This protein can form intracellular aggregates like tau and Abeta and is localized with pathological tau in AD brains. In Aim 3 we will test whether the localized overexpression of the amyloid beta (Abeta) protease neprilysin will interfere with amyloid deposition in mice transgenic for 2 human AD gene mutations that result in progressive accumulation of structures analogous to AD senile plaques. In Aim 4 we wiii use vectors to selectively overexpress individual species of Abeta that may either facilitate or interfere with accumulation of insoluble Abeta. This may help reveal why Abeta deposits fail to develop in a number of models in which it was expected but not found, and why it occurs naturally to some humans more than others. These studies are intended to increase our understanding of what determines whether AD occurs, in the absence of gene mutations. They also contribute to the development of future therapeutics, including potential gene therapy.

我们已经使用AAV载体在啮齿动物中产生与阿尔茨海默病（AD）相关的现象，并抵消AD病理学的方面。神经元缠结（NFT）在手术注射携带编码微管相关蛋白tau的基因中的人类突变的AAV载体的数周内发展。在注射携带淀粉样前体蛋白家族性AD突变的载体一年后发现记忆缺陷。基底前脑胆碱能神经元对于记忆是关键的，并且在AD中死亡，已经通过转导神经生长因子表达的AAV载体保护其免受年龄和损伤相关的功能丧失。我们现在建议使用这种基因转移技术来测试目标1中的蛋白磷酸酶2A的抑制是否会导致功能障碍， 体内tau的病理学。已发现这种酶的活性在AD中降低。目的2将测试发现在AD中选择性和实质性升高的神经元丝蛋白的过表达是否将诱导任何AD相关的解剖、行为或生化病理。这种蛋白质可以形成细胞内聚集体，如tau和Abeta，并与AD脑中的病理性tau一起定位。在目标3中，我们将测试淀粉样蛋白β（Abeta）蛋白酶脑啡肽酶的局部过表达是否会干扰转2个人AD基因突变的小鼠中的淀粉样蛋白沉积，所述突变导致类似于AD老年斑的结构的进行性积累。在目的4中，我们将使用载体来选择性地过表达可能促进或干扰不溶性Abeta积累的Abeta的单个种类。这可能有助于揭示为什么Abeta沉积物在许多预期但未发现的模型中未能发展，以及为什么它在某些人身上比其他人更自然地发生。这些研究 旨在增加我们对在没有基因突变的情况下，是什么决定AD是否发生的理解。它们还有助于未来治疗方法的发展，包括潜在的基因治疗。