PAPP-A as a Potential Target in Alzheimer's Disease

PAPP-A 作为阿尔茨海默病的潜在靶点

• 批准号: 10577483
• 负责人: Cheryl A. Conover
• 金额: $ 19.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577483
• 关键词: Acceleration; Age; Age Months; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapy; Amyloid beta-Protein; Astrocytes; Behavior; Behavioral; Brain; Brain Pathology; Data; Deposition; Development; Disease; Early Onset Alzheimer Disease; Emotional; Enzymes; Family; Friends; Gene Deletion; Genetic; Genotype; Heterozygote; Impaired cognition; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like-Growth Factor I Receptor; Knock-out; Knockout Mice; Link; Mediator; Memory Loss; Microglia; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligopeptides; Pathologic; Patients; Peptide Hydrolases; Pregnancy-Associated Plasma Protein-A; Psyche structure; Receptor Activation; Receptor Mediated Signal Transduction; Research; Role; Senile Plaques; Signal Transduction; Somatomedins; System; Transgenes; Transgenic Mice; amyloid formation; behavior test; cognitive change; cognitive function; effective therapy; extracellular vesicles; knock-down; mouse model; new therapeutic target; novel; novel therapeutics; object recognition; prevent

PROJECT SUMMARY Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease of age that is associated with formation of plaques and destruction of neurons in the brain, leading to severe memory loss and behavioral changes. Unfortunately and despite intensive research, there is no effective treatment for AD. A better understanding of the cellular mechanisms underlying the accumulation of toxic β-amyloid peptides and formation of amyloid plaque in AD is likely to identify potential new therapeutic targets. Rigorous prior research links the insulin-like growth factor (IGF) system to the accelerated progression of AD. Experimental AD in mice responds positively to reduction of IGF signaling through genetic means. Thus, deletion or knock-down of IGF-I receptors or intracellular mediators of receptor-mediated signal transduction in AD mice has been shown to reduce plaque formation in the brain and prevent/delay neurodegeneration and associated behavioral changes. We hypothesize that deletion of a novel proteolytic enzyme (PAPP-A), which enhances IGF action through cleavage of inhibitory IGF binding proteins, protects against AD-like pathology and behavior in mouse models of AD. For this proposal, we will generate AD mice combined with PAPP-A gene deletion. ATTPswe/PS1dE9 transgenic (AD) mice express mutations associated with early-onset AD, and develop β- amyloid deposits in brain by 6 to 7 months of age. Our established PAPP-A knock-out (KO) mice are crossed with the AD mice to get mice heterozygous for PAPP-A with or without AD transgenes. These mice are then crossed to get four genotypes for the study: Wild-type (WT), AD, PAPP-A KO, and AD/PAPP-A KO mice. Our preliminary data establish feasibility. Specific Aim 1. Determine the consequences of PAPP-A gene deletion on brain pathology in AD mice. At 6, 12, and 18 months of age, brains from WT, AD, PAPP-A KO and AD/PAPP-A KO mice will be analyzed for amyloid plaque, β-amyloid oligopeptides, and reactive astrocytes and activated microglia. In addition, brain IGF-I receptor activation and circulating PAPP-A in extracellular vesicles will be assessed. Specific Aim 2. Assess how PAPP-A gene deletion impacts cognitive function in AD mice. At 6, 12, and 18 months of age, WT, AD, PAPP-A KO, and AD/PAPP-A KO mice will undergo behavioral testing using novel object recognition and the Stone T-maze. The proposed studies would be the first to generate and characterize a mouse model to study the role of PAPP-A in AD. Demonstration that loss of PAPP-A expression impacts pathological changes and behavioral consequences would support the development of novel neurodegenerative therapies based on targeted inhibition of PAPP-A.

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种进行性、不可逆的老年性神经退行性疾病， 随着斑块的形成和大脑神经元的破坏，导致严重的记忆丧失， 行为改变不幸的是，尽管进行了深入的研究，但没有有效的治疗AD的方法。一 更好地理解毒性β-淀粉样肽积累的细胞机制， AD中淀粉样蛋白斑的形成可能识别潜在的新治疗靶点。严格的前期研究 将胰岛素样生长因子（IGF）系统与AD的加速进展联系起来。小鼠实验性AD 通过遗传手段对IGF信号传导的减少做出积极反应。因此，IGF-I的缺失或敲低 已显示AD小鼠中受体或受体介导的信号转导的细胞内介质 减少大脑中斑块的形成，预防/延缓神经变性和相关的行为 变化我们假设一种新型蛋白水解酶（PAPP-A）的缺失会增强IGF的作用 通过切割抑制性IGF结合蛋白，保护小鼠免受AD样病理和行为 AD模型针对这一提议，我们将产生与PAPP-A基因缺失相结合的AD小鼠。 ATTPswe/PS1 dE 9转基因（AD）小鼠表达与早发性AD相关的突变，并出现β- 6 - 7个月大时淀粉样蛋白沉积在大脑中。将我们建立的PAPP-A敲除（KO）小鼠杂交， 以获得PAPP-A杂合的有或没有AD转基因的小鼠。这些老鼠 杂交以获得用于研究的四种基因型：野生型（WT）、AD、PAPP-A KO和AD/PAPP-A KO小鼠。我们 初步数据确定了可行性。 具体目标1。确定PAPP-A基因缺失对AD小鼠脑病理学的影响。六点， 在12和18月龄时，将分析来自WT、AD、PAPP-A KO和AD/PAPP-A KO小鼠的脑， 淀粉样蛋白斑、β-淀粉样蛋白寡肽、反应性星形胶质细胞和活化的小胶质细胞。此外，大脑 将评估细胞外囊泡中的IGF-I受体活化和循环PAPP-A。 具体目标2。评估PAPP-A基因缺失如何影响AD小鼠的认知功能。在6岁，12岁，18岁时 月龄时，WT、AD、PAPP-A KO和AD/PAPP-A KO小鼠将使用新的免疫抑制剂进行行为测试。 物体识别和石头T型迷宫 拟议的研究将是第一个生成和表征小鼠模型以研究 AD中的PAPP-A。证明PAPP-A表达的丧失影响病理变化和行为 结果将支持基于靶向的新型神经退行性治疗的发展。 抑制PAPP-A。