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

Tau蛋白聚集是神经退行性疾病中最常见的病理改变。 统称为“紧张症”。这些疾病包括15种不同的疾病，它们极大地影响 退伍军人，包括阿尔茨海默病(AD)和创伤性脑损伤。最常见的原因是 痴呆症在美国，AD影响着500多万美国人，其中包括60万军事人员 每年耗资2000亿美元。有效的治疗策略仍然难以捉摸。我们正在使用新鲜的 不同学科的观点，并正在研究细胞衰老作为一种新的细胞应激 与tau相关的神经退变有关的反应。 含有tau的大而不溶的聚集体，神经原纤维缠结(Nfts)，是最接近的组织病理学。 与阿尔茨海默病的神经元丢失和认知功能下降有关。然而，因为含有NFT的神经元不会死亡， 它们在神经退行性变中的作用尚不清楚。我们认为，NFTs可能通过继发性、 非细胞自主机制。具体地说，我们认为含有NFT的细胞可能对组织有贡献 通过分泌有毒的可溶性因子进行破坏，其机制类似于细胞衰老。 细胞衰老的特征通常是永久性的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”已经被用来 描述与年龄相关的变化，包括胞体肿胀、树突棘丢失和进行性变化。 异常物质引起的“细胞质空间阻塞”；表型与含有NFT的一致 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 表型包括肿瘤抑制基因p16INK4a(P16)和炎性细胞因子的高表达。 研究表明，随着年龄的增长，衰老的细胞会导致组织损伤和功能衰退。 最近，我们发现携带NFTs的转基因小鼠的衰老标记显著增加。 脑，包括p16。P16的升高与脑细胞因子、肿瘤坏死因子α和白介素1β的升高有关。 只有患有NFT的小鼠，而不是年龄匹配的高水平可溶性tau的对照组小鼠，表现出衰老- 相关因素。总的来说，这些数据表明致病的tau和细胞衰老是 互联互通。研究的目的是阐明tau相关的发病机制是否会导致衰老- 与tau相关的脑部病理和行为缺陷相互作用的LIKE表型 神经退行性疾病。正在进行的转基因小鼠研究将集中在分子介体上 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病理、神经退行性变和认知衰退。 通过CDA-2中提出的活动，我将实现我的最终职业目标：成为一名 独立调查员致力于了解AD，同时改善健康和 退伍军人及其家人的福祉。我已经制定了一个全面的计划，在一个 优秀的指导团队。他们代表退伍军人事务部和AD、衰老和疾病研究的领导者 发炎。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 并为我的独立事业奠定了基础。我的指导团队将为我的职业发展辩护 在退伍军人事务部内，包括为我提供领导机会和支持我更大的社区 外展活动。年南得克萨斯州退伍军人医疗保健系统的特殊培训机会 圣安东尼奥和社区参与，为我的生活提供了一个理想的环境 作为一名全面发展的科学家的雄心。到CDA-2完成时，我预计将做好充分准备，以(1)领导 专注于AD的独立研究计划；(2)生成了足够的数据来竞争优点 评审获奖资金；(3)并加入退伍军人管理局的科研队伍。

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.