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

项目总结 阿尔茨海默病(AD)是一种进行性和不可逆转的老年神经退行性疾病，与 随着大脑中斑块的形成和神经元的破坏，导致严重的记忆丧失和 行为上的改变。不幸的是，尽管进行了大量的研究，但没有有效的治疗阿尔茨海默病的方法。一个 更好地理解有毒的β-淀粉样多肽和 AD中淀粉样斑块的形成可能识别潜在的新的治疗靶点。严谨的前期研究 将胰岛素样生长因子(IGF)系统与AD的加速进展联系起来。小鼠实验性阿尔茨海默病 对通过遗传方式减少的IGF信号有积极的反应。因此，IGF-I的删除或敲除 受体介导的信号转导的受体或细胞内介质已被证明在AD小鼠中 减少大脑中斑块的形成，预防/延缓神经退变和相关的行为 改变。我们假设一种新的蛋白水解酶(PAPP-A)的缺失可以增强IGF的作用 通过切割抑制性IGF结合蛋白，保护小鼠免受AD样病理和行为的影响 AD的模型。对于这个提议，我们将产生结合PAPP-A基因缺失的AD小鼠。 ATTPswe/PS1dE9转基因(AD)小鼠表达与早发性AD相关的突变，并发展为β- 6至7个月龄时大脑中有淀粉样物沉积。我们已建立的Papp-A基因敲除(KO)小鼠 用AD小鼠获得携带或不携带AD转基因的PAPP-A杂合子小鼠。然后这些老鼠就是 杂交得到四种基因类型：野生型(WT)、AD、PAPP-A KO和AD/PAPP-A KO小鼠。我们的 初步数据证实了这一点的可行性。 具体目的1.确定PAPP-A基因缺失对AD小鼠脑病理的影响。在6点， 12个月和18个月龄，WT、AD、PAPP-A KO和AD/PAPP-A KO小鼠的大脑将被分析 淀粉样斑块，β-淀粉样寡肽，反应性星形胶质细胞和激活的小胶质细胞。此外，大脑 将评估细胞外小泡中IGF-I受体的激活和循环中的PAPP-A。 具体目的2.评估PAPP-A基因缺失对AD小鼠认知功能的影响。在6、12和18 几个月龄的WT、AD、PAPP-A KO和AD/PAPP-A KO小鼠将接受使用新的 物体识别和石头T形迷宫。 这项拟议中的研究将是第一次建立和表征小鼠模型来研究阿片受体的作用。 AD中的Papp-A。PAPP-A表达缺失对病理改变和行为的影响 其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。

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.