Effects of PARP-1 gene deletion in a mouse model of Alzheimer's disease

描述（由申请方提供）：聚（ADP-核糖）聚合酶-1（简称PARP-1）是一种可被遗传毒性应激激活的核酶。PARP-1激活可以1）促进DNA修复; 2）诱导细胞死亡，或3）促进炎症，其中每一种都可能导致阿尔茨海默病的发病机制。在这里，我们将通过产生双转基因小鼠mAPPJ 20 x PARP-1-/-来研究PARP-1在阿尔茨海默病中的作用。mAPPJ 20品系小鼠表达与家族性阿尔茨海默病相关的突变型人淀粉样前体蛋白（mAPP）。这些小鼠发展成淀粉样斑块、小胶质细胞活化和认知障碍。缺乏PARP-1的小鼠在氧化应激条件下表现出减少的神经元死亡和减弱的小胶质细胞对许多刺激的反应，包括淀粉样蛋白聚集体。使用行为和组织学结局指标，将mAPPJ 20 x PARP-1-/-基因型小鼠与对照小鼠和来自两种亲本品系基因型的小鼠进行比较。具体目标如下：目标1：杂交现有的mAPPJ 20和PARP-1-/-小鼠品系以产生新的双转基因mAPPJ 20/PARP 1-/-小鼠品系目标2：量化这些小鼠中的年龄依赖性行为变化。目标3：量化这些小鼠的年龄依赖性组织学变化：斑块沉积、小胶质细胞活化、突触和神经元损失以及神经元DNA损伤。我们的工作假设是，相对于mAPPJ 20亲本品系，mAPPJ 20 x PARP-1-/-小鼠将表现出减少的小胶质细胞活化和减缓的认知障碍。然而，在PARP-1-/- x mAPPJ 20小鼠中，行为和组织学变化可能加剧而不是减弱。这一结果表明，小胶质细胞活化，或至少是由PARP-1调节的小胶质细胞活化的那些方面，是AD中的净有益事件。或者，观察到的PARP-1基因缺失的有害作用可能揭示PARP-1在神经元对淀粉样蛋白沉积的反应中的作用，因为PARP-1在神经元对DNA损伤和应激的反应中也很重要。该研究旨在评估PARP-1基因缺失对阿尔茨海默病发病机制的潜在影响。PARP-1基因缺失对阿尔茨海默病小鼠模型的影响 阿尔茨海默病是老年人认知障碍的主要原因。小胶质细胞是脑内常驻的炎性细胞。一些研究表明，小胶质细胞有助于阿尔茨海默氏病的进展，而其他研究表明，小胶质细胞具有有益的作用。我们将通过将具有阿尔茨海默病蛋白的小鼠与具有受损的小胶质细胞活化的小鼠繁殖，并检查后代的疾病进展来解决这一争议。这些研究的结果将有助于确定炎症在阿尔茨海默病中的作用以及抗炎药物改变这种疾病进程的潜力。

DESCRIPTION (provided by applicant): Poly(ADP-ribose) polymerase-1 (abbreviated as PARP-1) is a nuclear enzyme that is activated by genotoxic stress. PARP-1 activation can 1) facilitate DNA repair; 2) induce cell death, or 3) promote inflammation, each of which may contribute to the pathogenesis of Alzheimer's disease. Here we will investigate the role of PARP-1 in Alzheimer's disease by generating a double transgenic mouse, mAPPJ20 x PARP-1-/-. Mice of the mAPPJ20 strain express a mutant human amyloid precursor protein (mAPP) associated with familial Alzheimer's disease. These mice develop amyloid plaques, microglial activation, and cognitive impairment. Mice deficient in PARP-1 show reduced neuronal death under conditions of oxidative stress and attenuated microglial response to many stimuli, including ¿-amyloid aggregates. The mAPPJ20 x PARP-1-/- genotype mice will be compared to control mice and mice from the two parental strain genotypes using behavioral and histological outcome measures. The specific aims are as follows: Aim 1: Cross the existing mAPPJ20 and PARP-1-/- mouse strains to generate a new, double transgenic, mAPPJ20 / PARP1-/- mouse line Aim 2: Quantify age-dependent behavioral changes in these mice. Aim 3: Quantify age-dependent histological changes in these mice: plaque deposition, microglial activation, synapse and neuronal loss, and neuronal DNA damage. Our working hypothesis is that the mAPPJ20 x PARP-1-/- mice will exhibit reduced microglial activation and slowed cognitive impairment relative to the mAPPJ20 parental strain. However, it is possible that the behavioral and histological changes may be exacerbated, rather than attenuated, in the PARP-1-/- x mAPPJ20 mice. This result would suggest that microglial activation, or at least those aspects of microglial activation regulated by PARP-1, is a net beneficial event in AD. Alternatively, an observed deleterious effect of PARP-1 gene deletion could uncover a role for PARP-1 in the neuronal response to amyloid deposition, because PARP-1 is also important in neuronal responses to DNA damage and stress. The study is designed to evaluate each of these potential effects of PARP-1 gene deletion on the pathogenesis of Alzheimer's disease. Effects of PARP-1 gene deletion in a mouse model of Alzheimer's disease. Alzheimer's disease is the major cause of cognitive impairment in elderly adults. Microglia are the resident inflammatory cells in brain. Some studies have suggested that microglia contribute to the progression of Alzheimer's disease, whereas other studies suggest that microglia have a beneficial effect. We will address this controversy by breeding mice with an Alzheimer's disease protein with mice that have impaired microglia activation, and examining disease progression in the offspring. The results of these studies will help establish the role of inflammation in Alzheimer's disease and the potential for anti-inflammatory drugs to modify the course of this disease.