Integrated Neuroimaging and Pathology of Alzheimer Mice

描述（由申请人提供）：最近的研究表明，非甾体抗炎药（NSAIDs）可以延缓阿尔茨海默病（AD）的发病或延缓其进展，并减少过度表达人淀粉样蛋白前体蛋白（APPrg2576）的转基因小鼠的β淀粉样蛋白（AS）沉积。最近发表的工作和我们的初步研究表明，一些非甾体抗炎药减少了A β 1-42的产生，这是最具毒性的A β物种。尽管布洛芬降低了小鼠脑内A β 1-42 / A β 1-40的比值，但由于APPrg2576小鼠不发生神经原纤维缠结（NFT），因此尚不清楚布洛芬是否改变了神经变性的过程。此外，A β沉积和非甾体抗炎药对脑代谢的体内影响尚未研究。为了解决这些问题，我们建议使用最先进的磁共振波谱和成像（MRS， MRI）和正电子发射断层扫描技术来定量体内和体外的代谢标志物，在一个新的三重转基因小鼠模型中，该模型含有三个突变的人类基因：淀粉样蛋白前体蛋白（APPswe），早老素-1 （PS1M146V）和tauP301L，表达水平相当。这些小鼠积累A β，并形成类似于阿尔茨海默病的nft样细胞内tau沉积。我们将定义体内进行性AB沉积和NFT形成的代谢影响，以及布洛芬治疗对这些参数的影响。我们的初步研究表明，APPTg2576中n -乙酰天冬氨酸减少，牛磺酸增加。我们假设衰老小鼠的MRS谱会随着A β的积累而恶化，可能在NFT形成之前。MRS检测到的代谢变化、Aft沉积的定量测量和体内NFT的发展之间的分离可能表明非聚集的A β部分有助于神经元损伤。表征代谢、神经化学和神经病理变化的时间序列将使我们更好地了解非甾体抗炎药的神经保护作用，并有助于在未来设计更好的治疗AD的方法。

DESCRIPTION (provided by applicant): Recent studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may either delay onset or slow progression of Alzheimer's disease (AD) and reduce beta amyloid (AS) deposition in transgenic mice overexpressing human amyloid precursor protein (APPrg2576). Recently published work and our preliminary studies suggest that some NSAIDs reduce the generation of A beta 1-42, the most toxic A beta, species. Although, ibuprofen lowers A Beta 1-42 / A Beta 1-40 ratio in mouse brain it is not known if it alter the process of neurodegeneration because APPrg2576 mice do not develop neurofibrillary tangles (NFT). Furthermore, the in vivo effects of A Beta deposition and NSAIDs on brain metabolism have not been studied. To address these questions we propose to use state of the art magnetic resonance spectroscopy and imaging (MRS, MRI) and positron emission tomography technology to quantitate metabolic markers in vivo and in vitro in a novel triple transgenic mouse model that harbors three mutant human genes: amyloid precursor protein (APPswe), presenilin-1 (PS1M146V) and tauP301L expressed at comparable levels. These mice accumulate A Beta, and develop NFT-like intracellular tau deposits similar to those seen in AD. We will define the metabolic effects of progressive AB deposition and NFT formation in vivo and the effects of treatment with ibuprofen on these parameters. Our preliminary studies show decreased N-acetyl aspartate and increased taurine in APPTg2576. We hypothesize that the MRS profile of aging mice will deteriorate as A Beta accumulates, potentially prior to NFT formation. A dissociation between metabolic changes detected by MRS, quantitative measures of Aft deposition and the development of NFT in vivo may indicate that non-aggregated A Beta moieties contribute to neuronal injury. Characterizing the temporal sequence of metabolic, neurochemical and neuropathological changes will allow us to better understand the neuroprotective effects of NSAIDs and help design better treatments for AD in the future.