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

描述(申请人提供)：聚(ADP-核糖)聚合酶-1(简称PARP-1)是一种核酶，由遗传毒性应激激活。PARP-1的激活可以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。在这里，我们将通过产生一个双转基因小鼠mAPPJ20 x PARP-1-/-来研究PARP-1在阿尔茨海默病中的作用。MAPPJ20品系的小鼠表达一种突变的人类淀粉样前体蛋白(MAPP)，与家族性阿尔茨海默病有关。这些小鼠会出现淀粉样斑块、小胶质细胞激活和认知障碍。缺乏PARP-1的小鼠在氧化应激条件下神经元死亡减少，对包括淀粉样蛋白聚集体在内的许多刺激的小胶质细胞反应减弱。MAPPJ20 x PARP-1/-基因型的小鼠将通过行为和组织学结果指标与对照小鼠和来自两个亲本菌株基因型的小鼠进行比较。具体目标如下：目的1：将现有的mAPPJ20和PARP-1-/-小鼠品系杂交，建立一个新的双转基因mAPPJ20/PARP1-/-小鼠品系。目的2：量化这些小鼠的增龄行为变化。目的3：量化这些小鼠与年龄相关的组织学变化：斑块沉积、小胶质细胞激活、突触和神经元丢失以及神经元DNA损伤。我们的工作假设是，与mAPPJ20亲本品系相比，mAPPJ20 x PARP-1-/-小鼠的小胶质细胞激活减少，认知障碍减缓。然而，在PARP-1-/-x mAPPJ20小鼠中，行为和组织学变化可能会加剧，而不是减弱。这一结果表明，小胶质细胞的激活，或者至少是受PARP-1调节的小胶质细胞激活的那些方面，在AD中是一个净受益事件。或者，观察到的PARP-1基因缺失的有害影响可能揭示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是重要的。这项研究旨在评估PARP-1基因缺失在阿尔茨海默病发病机制中的每一种潜在影响。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。小胶质细胞是驻留在脑内的炎性细胞。一些研究表明，小胶质细胞有助于阿尔茨海默病的进展，而另一些研究则表明，小胶质细胞具有有益的影响。我们将通过用阿尔茨海默病蛋白与小胶质细胞激活受损的小鼠饲养小鼠来解决这一争议，并检查后代的疾病进展。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可能性。

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.