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“ tauopaties”。这些疾病包括超过15种不同影响的疾病 退伍军人，包括阿尔茨海默氏病（AD）和脑外伤。作为最常见的原因 美国的痴呆症会影响超过500万美国人，其中包括60万军人 每年耗资2000亿美元。有效的治疗策略仍然难以捉摸。我们正在申请新鲜 来自不同学科的观点，正在研究细胞感应作为一种新的细胞应激 与Tau相关的神经变性涉及的响应。 大型不溶性含Tau的聚集体，神经纤维缠结（NFTS）是最接近的组织病理学 与AD的神经元丧失和认知下降相关。但是，由于具有NFT神经元不会死亡，所以 它们在神经变性中的作用尚不清楚。我们建议NFT可以通过次级引起毒性， 非电池自主机制。具体而言，我们建议含NFT的细胞可能有助于组织 通过与细胞感应相似的机制分泌有毒固体因子的破坏。 细胞感应通常以永久性细胞周期停滞和基因改变的特征。 表达，代谢状态，形态和细胞因子分泌。在神经元中，“敏感”已用于 描述与年龄相关的变化，包括躯体肿胀，树突状刺和进步 具有异常材料的“细胞质空间窒息”；表型与含NFT的表型非常吻合 神经元。虽然没有单个统一标记来定义复杂的感应应力响应，但鲁棒 表型包括肿瘤抑制p16INK4A（P16）和炎症细胞因子的基因表达升高。 研究表明，感觉细胞随着年龄的增长而导致组织损伤和功能下降。 最近，我们发现具有NFTS的转基因小鼠的感应标记具有显着升高 大脑，包括p16。 p16的增加与脑细胞因子，TNFα和IL1β的升高有关。 仅具有NFT的小鼠，而不具有高水平固体tau的年龄匹配的对照，表达衰老 - 相关因素。总的来说，这些数据表明致病性tau和细胞感应是 互联。研究目标是阐明与tau相关的发病机理是否诱发了感应 就像相互促进脑病理学的表型和行为相关的行为定义 神经退行性疾病。正在进行的转基因小鼠的研究将集中于分子介质 大脑中的细胞感应，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，神经退行性和认知能力下降。 通过此CDA-2提出的活动，我将实现我的最终职业目标：成为一个 独立研究者致力于追求了解广告的同时改善健康和 退伍军人及其家人的福祉。我制定了一个全面的计划，在 出色的心理团队。它们代表VA中的领导者以及AD，衰老和研究的研究 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 并为我的独立职业奠定基础。我的心理团队将倡导我的职业发展 在VA中，包括为我提供领导机会和支持我的更大社区的机会 外展活动。南德克萨斯州退伍军人卫生保健系统的出色培训机会 圣安东尼奥（San Antonio）以及社区参与“美国军事城市”，为我提供了理想的环境 作为一位全面的科学家的野心。我希望在CDA-2的完成后做好充分的准备（1）铅 一项针对AD的独立研究计划； （2）产生了足够的数据以争夺优异 审查奖资金； （3）并加入了VA科学劳动力。