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

Abeta、tau 和 mTOR 之间的分子相互作用：神经退行性变的机制

• 批准号: 8184486
• 负责人: Salvatore Oddo
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8184486
• 关键词: Address; Adrenergic Receptor; Alleles; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Behavioral; Brain; Brain region; Cause of Death; Clinical Treatment; Cognitive; Cognitive deficits; Data; Dementia; Deterioration; Disease; Elderly; Epidemiologic Studies; Event; Genes; Genetic; Genetic Polymorphism; Homeostasis; Human; Hyperactive behavior; Impaired cognition; In Vitro; Incidence; Knock-out; Late Onset Alzheimer Disease; Lead; Learning; Link; Mediating; Memory; Memory Loss; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Process; Protein Biosynthesis; Proteins; Receptor Signaling; Role; Senile Plaques; Signal Transduction; Sirolimus; Testing; Tg2576; United States; base; cognitive function; high risk; hyperphosphorylated tau; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; mTOR protein; mouse model; new therapeutic target; overexpression; protein aggregate; protein degradation; research study; tau Proteins; tau aggregation; tau mutation; therapeutic target; transgenic model of alzheimer disease

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.

描述（由适用提供）：阿尔茨海默氏病（AD）脑的特征是两种类型的蛋白质聚集体，神经原纤维缠结（NFTS），由高磷酸化的tau和淀粉样蛋白块组成，由淀粉样蛋白块组成。在临床上，AD患者显示出记忆和其他认知功能的逐步影响。最近的证据表明，固体是最初触发记忆力损失的绝佳候选者；然而，诱导的认知下降基础的分子机制仍然难以捉摸。在我们的初步研究中，我们已经确定雷帕霉素（MTOR）的哺乳动物靶标是A？，TAU和认知能力下降之间的潜在分子联系。此外，我们表明A寡聚物增加了MTOR信号传导，这是由2种肾上腺素受体（2ARS）介导的事件。为了确定MTOR信号传导与A，TAU和认知能力下降之间的机械联系，提出了三个具体目标：具体目标1将检验以下假设：A poligomers的积累通过通过«2ARS介导的机制增加MTOR活性。 MTOR在调节蛋白质稳态方面起关键作用；因此，揭示导致其在AD失调的分子途径将使人们更好地了解疾病发病机理。在这里，我们将剖析将A积累与2ARS/mTOR信号传导变化联系起来的分子途径。特定的目标2将检验以下假设：A诱导的MTOR信号的增加进一步增加了病理学并加剧了认知能力下降。我们的初步数据表明，在3XTG-AD和TG2576小鼠中，MTOR信号传导增加。此外，我们表明，选择性MTOR抑制剂雷帕霉素减少MTOR信号传导，反应了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独立的作用。为了直接解决MTOR在AD中的作用，我们将在TG2576小鼠的大脑中使用遗传方法和敲除MTOR。具体目标3将检验以下假设：MTOR信号的增加直接有助于TAU病理。我们的初步数据表明，恢复3XTG-AD小鼠中的MTOR信号传导会遭受减少A级和TAU病理的苦难。但是，这些小鼠的tau病理高度取决于A水平。因此，是否要确定恢复MTOR信号传导对Tau病理学的影响是由MTOR和TAU之间的直接相互作用介导的，还是仅仅是由于A水平的降低而引起的。使用过表达野生型TAU的小鼠模型，我们将使用遗传和药物方法来降低MTOR信号传导并测试MTOR信号传导与TAU病理学之间的机械联系。总体而言，拟议的特定目标将阐明与A，TAU和认知能力下降相关的基本分子途径。识别导致认知能力下降的途径可能指出了新的治疗靶标。 公共卫生相关性：阿尔茨海默氏病是美国最古老和第七大死亡原因中最常见的痴呆形式。我们的研究旨在了解AD下降的分子基础记忆丧失和认知能力，并将促进这种阴险疾病的潜在治疗靶标的鉴定。