Molecular interplay between Abeta, tau and mTOR: Mechanisms of neurodegeneration

描述（由申请人提供）：阿尔茨海默病（AD）脑的特征在于两种类型的蛋白质聚集体，即由过度磷酸化的tau组成的神经元缠结（NFT）和由淀粉样蛋白-<$（A <$）组成的淀粉样蛋白斑块。临床上，AD患者表现出记忆和其他认知功能的进行性恶化。最近的证据表明，可溶性A？作为记忆丧失的初始触发因素的一个很好的候选者;然而，A？诱导的认知能力下降的分子机制仍然难以捉摸。在我们的初步研究中，我们已经确定了哺乳动物雷帕霉素靶蛋白（mTOR）作为A？，tau和认知能力下降之间的潜在分子联系。此外，我们发现A？寡聚体增加mTOR信号传导，这是由？2肾上腺素能受体（？2AR）介导的事件。为了确定mTOR信号传导与A？、tau和认知衰退之间的机制联系，提出了三个特定目的：特定目的1将检验A？寡聚体的积累通过由A？2AR介导的机制增加mTOR活性的假设。mTOR在调节蛋白质稳态中起着关键作用;因此，揭示AD中导致其失调的分子途径将有助于更好地理解疾病的发病机制。在这里，我们将剖析的分子途径，连接的A ²积累的变化，在² 2AR/mTOR信号。具体目标2将检验以下假设：A？诱导的mTOR信号传导增加进一步增加A？病理学并加剧认知能力下降。我们的初步数据显示，mTOR信号在3xTg-AD和Tg 2576小鼠中增加。此外，我们发现，用雷帕霉素（一种选择性mTOR抑制剂）减少mTOR信号传导，可以挽救6个月大的3xTg-AD小鼠的早期神经病理学和行为表型。越来越多的证据表明，雷帕霉素可能具有mTOR非依赖性效应。为了直接解决mTOR在AD中的作用，我们将使用遗传方法并在Tg 2576小鼠的大脑中敲除mTOR。具体目标3将检验mTOR信号传导的增加直接促成tau病理学的假设。我们的初步数据表明，在3xTg-AD小鼠中恢复mTOR信号传导足以减少A和tau病理。然而，这些小鼠中的tau病理学高度依赖于A水平;因此，恢复mTOR信号传导对tau病理学的影响是否由mTOR和tau之间的直接相互作用介导，或者仅仅是由于A水平的降低，仍有待确定。使用过表达野生型tau的小鼠模型，我们将使用遗传和药理学方法来减少mTOR信号传导，并测试mTOR信号传导和tau病理之间的机制联系。总的来说，提出的具体目标将阐明连接A？，tau和认知衰退的潜在分子途径。识别导致认知能力下降的途径可能会指向新的治疗靶点。 公共卫生相关性：阿尔茨海默病是老年人中最常见的痴呆症，也是美国第七大死亡原因。我们的研究旨在了解AD衰退中记忆丧失和认知的分子基础，并将有助于确定这种潜在疾病的潜在治疗靶点。

DESCRIPTION (provided by applicant): The Alzheimer disease (AD) brain is characterized by two types of protein aggregates, neurofibrillary tangles (NFTs), comprised of hyperphosphorylated tau, and amyloid plaques, comprised of amyloid-¿ (A¿). Clinically, AD patients show a progressive deterioration of memory and other cognitive functions. Recent evidence points to soluble A¿ as an excellent candidate for the initial trigger of memory loss; however, the molecular mechanisms underlying A¿ -induced cognitive decline remain elusive. In our preliminary studies, we have identified the mammalian target of rapamycin (mTOR) as a potential molecular link between A¿, tau and cognitive decline. Additionally, we show that A¿ oligomers increase mTOR signaling, an event mediated by the ¿2 adrenergic receptors (¿2ARs). To identify the mechanistic link between mTOR signaling and A¿, tau and cognitive decline, three Specific Aims are proposed: Specific Aim 1 will test the hypothesis that the accumulation of A¿ oligomers increases mTOR activity by a mechanism mediated by ¿2ARs. mTOR plays a key role in regulating protein homeostasis; thus, unveiling the molecular pathways leading to its deregulation in AD will lead to a better understanding of the disease pathogenesis. Here we will dissect the molecular pathways that link the A¿ accumulation to changes in ¿2ARs/mTOR signaling. Specific Aim 2 will test the hypothesis that the A¿ -induced increase in mTOR signaling further increases A¿ pathology and exacerbates cognitive decline. Our preliminary data show that mTOR signaling is increased in 3xTg-AD and Tg2576 mice. Additionally, we show that reducing mTOR signaling with rapamycin, a selective mTOR inhibitor, rescues the early neuropathological and behavioral phenotypes in 6-month-old 3xTg-AD mice. Growing evidence shows that rapamycin may have mTOR-independent effects. To directly address the role of mTOR in AD, we will use a genetic approach and knockout mTOR in the brain of the Tg2576 mice. Specific Aim 3 will test the hypothesis that the increase in mTOR signaling directly contributes to the tau pathology. Our preliminary data show that restoring mTOR signaling in the 3xTg-AD mice suffices to reduce A¿ and tau pathology. However, the tau pathology in these mice is highly dependent on A¿ levels; therefore, it remains to be established whether the effects of restoring mTOR signaling on tau pathology are mediated by a direct interaction between mTOR and tau or are simply due to a decrease in A¿ levels. Using a mouse model overexpressing wild type tau, we will use genetic and pharmacological approaches to decrease mTOR signaling and test the mechanistic link between mTOR signaling and tau pathology. Overall, the proposed Specific Aims will elucidate the underlying molecular pathways linking A¿, tau and cognitive decline. The identification of the pathways that lead to cognitive decline may point to new therapeutic targets. PUBLIC HEALTH RELEVANCE: Alzheimer disease is the most common form of dementia among the elderly and the seventh leading cause of death in the United States. Our studies are aimed at understanding the molecular basis underlying memory loss and cognitive in AD decline and will facilitate the identification of potential therapeutic targets for this insidious disorder.