Effects of Conditional GSK3 Knockout on the Pathogenesis of Alzheimers Disease

描述(申请人提供)：阿尔茨海默病(AD)是一种神经退行性疾病，其特征是认知能力下降，最终发展为痴呆症。AD病理被认为是不溶性淀粉样斑块和神经原纤维缠结堆积的结果。最近的研究表明，两个高度相关的蛋白激酶，糖原合成酶激酶-31和2(GSK-31和GSK-32)，在调节2-淀粉样肽的产生中发挥了作用。这些分子以前被直接牵涉到神经纤维缠结的形成，表明GSK-3亚型是AD病理的重要介质。我们的长期目标是更好地了解GSK-3活性在AD发病机制中的作用。作为实现这一长期目标的一步，我们已经创造了可以有条件地敲除GSK-31和GSK-32的小鼠。我们想要检验的具体假设是，GSK-31的失活减少了2-淀粉样肽的产生，防止了AD病理的发生。这些小鼠，以及从这些小鼠衍生的细胞，将使我们能够开始研究GSK-3活性如何参与AD发病和神经退化的分子基础。具体目标1：确定每个GSK-3亚型在导致阿尔茨海默病发病机制的事件中的作用。具体目标2：描述GSK-31和GSK-32对2-淀粉样多肽产生的不同影响的分子基础。具体目标3：研究有条件地删除GSK-31和GSK-32在阿尔茨海默病发病机制中的作用。以上提出的目标利用我们的新型GSK-3条件性基因敲除小鼠，从而为我们在理解GSK-3亚型参与阿尔茨海默病的分子机制方面取得重大进展提供了机会。与公共健康相关：这项申请提出了一些实验，旨在更好地了解阿尔茨海默病是如何发展起来的。我们希望，这些知识的增加将导致能够减缓或预防与阿尔茨海默病相关的症状的治疗方法的发展。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease characterized by a deterioration of cognitive skills, eventually progressing to dementia. AD pathology is believed to result from an accumulation of insoluble amyloid plaques and neurofibrillary tangles. Recent studies have demonstrated a role for two highly related protein kinases, glycogen synthase kinase-31 and 2 (GSK-31 and GSK-32), in the regulation of 2-amyloid peptide production. These molecules have previously been directly implicated in neurofibrillary tangle formation, suggesting that GSK-3 isoforms are important mediators of AD pathology. Our long-term goal is to better understand how GSK-3 activity contributes to the pathogenesis of AD. As a step toward attaining this long-term goal, we have created mice that will allow for the conditional knockout of both GSK-31 and GSK-32. The specific hypothesis we wish to test is that inactivation of GSK-31 decreases 2-amyloid peptide production and prevents the onset of AD pathology. These mice, and the cells derived from these mice, will permit us to begin addressing the molecular basis of how GSK-3 activity contributes to AD pathogenesis and neurodegeneration. Specific Aim 1: Define the contribution of each GSK-3 isoform toward the events leading to the pathogenesis of Alzheimer's disease. Specific Aim 2: Delineate the molecular basis of the differential effects of GSK-31 and GSK-32 on the production of 2-amyloid peptides. Specific Aim 3: Examine the effects of conditionally deleting GSK-31 and GSK-32 on the pathogenesis of Alzheimer's disease. The aims proposed above utilize our novel GSK-3 conditional knockout mice, thus affording us an opportunity to make significant strides toward understanding the molecular mechanism by which GSK-3 isoforms participate in Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This application proposes experiments designed to gain a better understanding of how Alzheimer's disease develops. It is our hope that this increased knowledge will lead to the development of therapeutics capable of slowing or preventing the symptoms associated with Alzheimer's disease.