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: 7796643
• 负责人: Michael A King
• 金额: $ 21.39万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 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/7796643
• 关键词: Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Behavioral; Biochemical; Biological Assay; Brain Diseases; Deposition; Development; Disease; Disease model; Functional disorder; Future; Gel; Gene Mutation; Gene Transfer; Genes; Human; Hybrids; Individual; Injection of therapeutic agent; Injury; Laboratories; Memory; Memory impairment; Methods; Modeling; Mutation; Neprilysin; Nerve Growth Factors; Neurofibrillary Tangles; Neurons; Operative Surgical Procedures; Pathology; Peptide Hydrolases; Pharmaceutical Preparations; Plasmids; Preparation; Production; Protein Precursors; Protein phosphatase; Proteins; Quality Control; Recombinants; Rodent; Senile Plaques; Serotyping; Silver Staining; Structure; Technology; Testing; Therapeutic; Transfection; Transgenic Mice; Virus; adeno-associated viral vector; basal forebrain; enzyme activity; gene therapy; improved; in vivo; loss of function; neuronal thread protein; novel; overexpression; particle; programs; recombinant virus; tau Proteins; 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载体在啮齿类动物中产生与艾兹海默病(AD)相关的现象，并抵消AD病理方面的影响。神经原纤维缠结(NFT)在手术注射携带人类微管相关蛋白tau基因突变的AAV载体后的几周内形成。在注射了携带淀粉样前体蛋白家族AD突变的载体一年后，发现了记忆缺陷。基底前脑选择性神经元是记忆的关键，在AD中死亡，通过AAV载体转导神经生长因子的表达，可以保护它们免受年龄和损伤相关的功能丧失。我们现在建议在目标1中使用这种基因转移技术来测试蛋白磷酸酶2A的缺失是否会导致功能障碍和 活体内tau的病理学。这种酶的活性已被发现在阿尔茨海默病中降低。目的2将测试在AD中发现的选择性和实质性升高的神经元线程蛋白的过度表达是否会导致任何与AD相关的解剖、行为或生化病理。这种蛋白可以形成像tau和Abeta一样的细胞内聚集体，并与AD大脑中的病理性tau一起定位。在目标3中，我们将测试淀粉样β蛋白(Abeta)蛋白水解酶neprilysin的局部过表达是否会干扰转2个人类AD基因突变的小鼠的淀粉样沉积，这会导致类似AD老年斑的结构的进行性积累。在目标4中，我们将使用载体来选择性地过度表达个别物种的Abeta，这可能会促进或干扰不溶性Abeta的积累。这可能有助于揭示为什么在许多模型中未能形成Abeta沉积，在这些模型中，它被预期但没有被发现，以及为什么它在一些人身上比其他人更自然地发生。这些研究是 旨在增加我们对在没有基因突变的情况下决定AD是否发生的因素的理解。它们还有助于未来疗法的发展，包括潜在的基因疗法。