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: 9352624
• 负责人: Miranda Ethel Orr
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 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/9352624
• 关键词: Ablation; Acute; Advocate; Affect; Age; Agreement; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Attention; Autopsy; Award; Behavioral; Brain; Brain Pathology; CDKN2A gene; Cell Aging; Cell Cycle Arrest; Cells; Cellular Stress; Chimeric Proteins; Choking; Chronic; Chronic stress; Cities; Communities; Community Outreach; Complex; Data; Dementia; Dendritic Spines; Discipline; Disease; Elderly; Ensure; Environment; Family; Foundations; Functional disorder; Funding; Gene Expression; Goals; Health; Healthcare Systems; Histologic; Immersion Investigative Technique; Impaired cognition; In Vitro; Incidence; Inflammation; Inflammatory; Intercellular Fluid; Interleukin-1 beta; Label; Lead; Leadership; Life; Mediator of activation protein; Mentors; Mentorship; Metabolic; Microdialysis; Military Personnel; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Performance; Phenotype; Prevention strategy; Psychological Stress; Records; Reporter; Reproducibility; Research; Research Personnel; Role; Scientist; South Texas; Stress; Swelling; TNF gene; Talents; Tauopathies; Technical Expertise; Testing; Time; Tissues; Toxic effect; Transgenic Mice; Trauma; Traumatic Brain Injury; Tumor Suppressor Proteins; United States; Veterans; War; age related; biological adaptation to stress; brain tissue; career; career development; cell type; cost; cytokine; effective therapy; fighting; functional decline; functional improvement; improved; in vivo; innovation; mouse model; neurofibrillary tangle formation; neuron loss; neuronal cell body; neurotoxic; novel; novel therapeutic intervention; preclinical study; programs; protein aggregation; senescence; small molecule; socioeconomics; success; tau Proteins; tau aggregation; tau mutation; training opportunity; treatment strategy

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， 统称为“tau蛋白病”。这些疾病包括超过15种不同的疾病， 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，AD影响了500多万美国人，包括60万军事人员 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，并正在研究细胞衰老作为一种新的细胞应激 与tau相关的神经退行性变相关的反应。 大的不溶性含tau蛋白的聚集体，神经纤维缠结（NFT），是最接近的组织病理学 与AD中的神经元损失和认知下降相关。然而，由于含有NFT的神经元不会死亡， 它们在神经变性中的作用仍不清楚。我们认为NFT可能通过继发性， 非细胞自主机制。具体地说，我们提出，含有NFT的细胞可能有助于组织 通过分泌有毒的可溶性因子以类似于细胞衰老的机制进行破坏。 细胞衰老通常以细胞周期的永久停滞和基因突变为特征。 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 描述了与年龄相关的变化，包括索马肿胀，树突棘丢失，以及进行性 异常物质“细胞质空间阻塞”;表型与含NFT的 神经元虽然没有单一的统一标志物来定义复杂的衰老应激反应，但鲁棒性的是， 表型包括肿瘤抑制因子p16 INK 4a（p16）和炎性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。 脑，包括p16。p16的增加与脑细胞因子TNFα和IL 1 β的升高有关。 只有患有NFT的小鼠，而不是具有高水平可溶性tau的年龄匹配的对照组，表达衰老。 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 相互关联研究目标是阐明tau相关的发病机制是否诱导衰老- 类似的表型导致tau相关的脑病理和行为缺陷， 神经退行性疾病正在进行的转基因小鼠的研究将集中在分子介质， 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械相互作用 衰老、tau病理学、神经变性和认知衰退。 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 致力于追求了解AD，同时改善健康的独立调查员， 退伍军人及其家属的福利。我已经制定了一个全面的计划，由一个 优秀的指导团队。他们代表了退伍军人管理局和AD，衰老和 炎症通过计划的活动，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。我的指导团队将为我的职业发展提供支持 包括为我提供领导机会和支持我的更大社区 外联活动。南德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“军事城市，美国”，提供了一个理想的环境，我 作为一个全面发展的科学家的抱负。到CDA-2完成时，我预计将做好充分准备，（1）领导 专注于AD的独立研究计划;（2）已生成足够的数据来竞争Merit 审查奖资金;（3）并加入了VA科学劳动力。