Alzheimer’s disease-associated tau toxicity induces cellular senescence in the brain.

阿尔茨海默病相关的 tau 蛋白毒性会导致大脑细胞衰老。

• 批准号: 10132465
• 负责人: Miranda Ethel Orr
• 金额: --
• 依托单位: W G HEFNER VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132465
• 关键词: Alzheimer; disease; associated; tau; toxicity

Tau protein aggregation is the most common pathology among neurodegenerative diseases, which collectively are termed “tauopathies.” These diseases encompass over 15 distinct disorders that greatly affect Veterans, including Alzheimer's disease (AD) and traumatic brain injury. As the most common cause of dementia in the United States, AD affects more than 5 million Americans, including 600,000 military personnel and costs $200 billion per year. Effective treatment strategies remain elusive. We are applying fresh perspectives from different disciplines and are investigating cellular senescence as a novel cell stress response involved in tau-associated neurodegeneration. Large insoluble tau-containing aggregates, neurofibrillary tangles (NFTs), are the closest histopathological correlate with neuron loss and cognitive decline in AD. However, because NFT-containing neurons do not die, their role in neurodegeneration remains unclear. We suggest that NFTs may evoke toxicity through secondary, non-cell autonomous mechanisms. Specifically, we propose that NFT-containing cells may contribute to tissue destruction by secreting toxic soluble factors in a mechanism similar to cellular senescence. Cellular senescence is generally characterized by a permanent cell cycle arrest and alterations in gene expression, metabolic state, morphology, and cytokine secretion. In neurons, “senescence” has been used to describe age-associated changes that include swelling of the soma, loss of dendritic spines, and progressive “choking of cytoplasmic space” with abnormal material; phenotypes in good agreement with NFT-containing neurons. While there is no single unifying marker that defines the complex senescence stress response, robust phenotypes include elevated gene expression of tumor suppressor p16INK4a (p16) and inflammatory cytokines. Studies have illustrated that senescent cells contribute to tissue damage and functional decline with age. Recently, we found that transgenic mice with NFTs have a significant elevation in senescence markers in the brain, including p16. The increase in p16 was associated with an elevation in brain cytokines, Tnfα and Il1β. Only mice with NFTs, but not age-matched controls with high levels of soluble tau, expressed senescence- associated factors. Collectively, these data suggest that pathogenic tau and cellular senescence are interconnected. The research goal is to elucidate whether tau-associated pathogenesis induces a senescence- like phenotype that reciprocally contributes to brain pathology and behavioral deficits in tau-associated neurodegenerative diseases. Ongoing studies with transgenic mice will focus on molecular mediators of cellular senescence in the brain, specific cell types involved and the mechanistic interplay among cellular senescence, tau pathology, neurodegeneration and cognitive decline. Through the activities proposed in this CDA-2, I will achieve my ultimate career goal: to become an independent investigator dedicated to the pursuit of understanding AD while improving the health and wellbeing of Veterans and their families. I have developed a comprehensive program, guided by an outstanding mentoring team. They represent leaders within the VA and in the research of AD, senescence and inflammation. Through the planned activities, I will acquire new technical skills to achieve my research goals and lay the foundation for my independent career. My mentoring team will advocate for my career development within the VA, including providing me opportunities for leadership and supporting my greater community outreach activities. The exceptional training opportunities at the South Texas Veterans Health Care System in San Antonio, and community involvement in “Military City, USA”, provide an ideal environment for my ambitions as a well-rounded scientist. By the completion of the CDA-2 I expect to be fully prepared to (1) lead an independent research program focused on AD; (2) have generated sufficient data to compete for Merit Review Award funding; (3) and joined the VA scientific workforce.

Tau 蛋白聚集是神经退行性疾病中最常见的病理学， 统称为“tau蛋白病”。这些疾病涵盖超过 15 种不同的疾病，极大地影响 退伍军人，包括阿尔茨海默病 (AD) 和创伤性脑损伤。作为最常见的原因 在美国，痴呆症影响了超过 500 万美国人，其中包括 60 万军人 每年花费 2000 亿美元。有效的治疗策略仍然难以捉摸。我们正在申请新鲜 来自不同学科的观点，正在研究细胞衰老作为一种新的细胞应激 与 tau 相关的神经变性有关的反应。 含有大的不溶性 tau 蛋白的聚集体，神经原纤维缠结 (NFT)，是最接近的组织病理学 与 AD 中的神经元损失和认知能力下降相关。然而，由于含有 NFT 的神经元不会死亡， 它们在神经退行性变中的作用仍不清楚。我们认为 NFT 可能会通过二次、 非细胞自主机制。具体来说，我们提出含有 NFT 的细胞可能有助于组织 通过以类似于细胞衰老的机制分泌有毒可溶性因子来破坏。 细胞衰老的一般特征是永久性细胞周期停滞和基因改变 表达、代谢状态、形态和细胞因子分泌。在神经元中，“衰老”被用来 描述与年龄相关的变化，包括躯体肿胀、树突棘丧失和进行性 异常物质“堵塞细胞质空间”；表型与含有 NFT 的表型非常一致 神经元。虽然没有单一的统一标记来定义复杂的衰老应激反应，但稳健的 表型包括肿瘤抑制因子 p16INK4a (p16) 和炎症细胞因子的基因表达升高。 研究表明，随着年龄的增长，衰老细胞会导致组织损伤和功能下降。 最近，我们发现带有 NFT 的转基因小鼠的衰老标志物显着升高。 大脑，包括 p16。 p16 的增加与脑细胞因子、Tnfα 和 Il1β 的升高相关。 只有具有 NFT 的小鼠，而不是具有高水平可溶性 tau 的年龄匹配的对照小鼠，才表现出衰老。 相关因素。总的来说，这些数据表明致病性 tau 蛋白和细胞衰老是 互联。研究目标是阐明 tau 相关发病机制是否会导致衰老 与 tau 相关的表型相互促进大脑病理学和行为缺陷 神经退行性疾病。正在进行的转基因小鼠研究将集中于分子介质 大脑中的细胞衰老、涉及的特定细胞类型以及细胞之间的机制相互作用 衰老、tau 蛋白病理学、神经退行性变和认知能力下降。 通过本 CDA-2 中提出的活动，我将实现我的最终职业目标：成为一名 独立研究者致力于追求理解 AD，同时改善健康和 退伍军人及其家人的福祉。我制定了一个综合计划，由 优秀的导师团队。他们代表 VA 以及 AD、衰老和疾病研究领域的领导者 炎。通过计划的活动，我将获得新的技术技能以实现我的研究目标 为我的独立事业打下基础。我的导师团队将支持我的职业发展 在退伍军人事务部内，包括为我提供领导机会和支持我的更大社区 外展活动。南德克萨斯退伍军人医疗保健系统的特殊培训机会 圣安东尼奥以及“美国军事城市”的社区参与为我提供了理想的环境 成为一名全面发展的科学家的抱负。完成 CDA-2 后，我希望做好充分准备：(1) 领导 专注于 AD 的独立研究项目； (2) 已生成足够的数据来竞争 Merit 评审奖资助； (3)并加入了VA科学队伍。