Effects of Conditional GSK3 Knockout on the Pathogenesis of Alzheimers Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，其特征在于认知能力的退化，最终进展为痴呆。AD病理学被认为是由不溶性淀粉样蛋白斑块和神经纤维缠结的积累引起的。最近的研究表明，两种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β 2-淀粉样肽产生中的作用。这些分子以前直接参与神经元缠结的形成，表明GSK-3亚型是AD病理学的重要介质。我们的长期目标是更好地了解GSK-3活性如何促进AD的发病机制。作为实现这一长期目标的一步，我们创造了允许GSK-31和GSK-32条件性敲除的小鼠。我们希望检验的具体假设是GSK-31的失活减少了β 2-淀粉样肽的产生并防止了AD病理的发生。这些小鼠和来自这些小鼠的细胞将使我们能够开始解决GSK-3活性如何促进AD发病机制和神经退行性变的分子基础。具体目标1：明确GSK-3各亚型对阿尔茨海默病发病机制的作用。具体目标2：阐明GSK-31和GSK-32对2-淀粉样肽产生不同作用的分子基础。具体目标3：检查条件性缺失GSK-31和GSK-32对阿尔茨海默病发病机制的影响。上述提出的目标利用我们的新型GSK-3条件性敲除小鼠，从而为我们提供了一个机会，使我们在了解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。 公共卫生相关性：该应用程序提出了旨在更好地了解阿尔茨海默病如何发展的实验。我们希望，这一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.