Senescence-Induced Progression of Alzheimer's Disease

衰老引起的阿尔茨海默病进展

• 批准号: 10044094
• 负责人: Gavin Yong Wang
• 金额: $ 37.63万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10044094
• 关键词: 3xTg-AD mouse; AD transgenic mice; Abbreviations; Address; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid beta-Protein; Animal Model; Astrocytes; Attenuated; Automobile Driving; Behavioral; Biochemical; Biological Assay; Brain; Cell Aging; Cell model; Cells; Clinical; Cognitive; Complex; Confocal Microscopy; Cytometry; Defect; Dementia; Development; Disease; Disease Progression; Etiology; Excision; Genetic; Goals; Human; Immunofluorescence Microscopy; Impaired cognition; Impairment; Innovative Therapy; Intervention; Knowledge; Link; Magnetic Resonance Imaging; Mitochondrial DNA; Molecular Target; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Outcome Study; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pharmacology; Phenotype; Publishing; Role; Senile Plaques; Symptoms; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Work; age related; age related neurodegeneration; aging brain; base; cell type; cognitive function; effective therapy; healthy aging; human old age (65+); induced pluripotent stem cell; innovation; insight; mouse model; neurotoxicity; novel; novel therapeutic intervention; oxidative DNA damage; pre-clinical; prevent; senescence; stem cell proliferation; stem cells; targeted treatment; tau Proteins; three dimensional cell culture; transgenic model of alzheimer disease

Project Description Alzheimer's disease (AD) is an age-related neurodegenerative disorder featuring progressive cognitive, functional, and behavioral defects. Currently, more than 5.6 million Americans suffer from AD, and this number is projected to increase to 15.0 million by 2060. Despite several clinical interventions have been approved for treatment of AD, unfortunately they have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods with none showing a clear therapeutic effect on disease progression. The lack of a clear understanding of the mechanisms driving the pathogenesis and progression of AD is a significant barrier to the development of innovative and effective therapies. The goal of this proposal is to address this gap by defining the role of senescence in brain aging and AD pathogenesis. My lab and those of others have shown that the number of senescent cells was markedly increased in the brain of AD patients and that the removal of senescent cells can prevent cognitive declines and attenuate AD pathology in preclinical animal models. These results suggest a critical role for senescent cells in AD pathogenesis and treatment. Based on evidence provided by us and others that 1) oxidative stress is a pathological feature of AD, and 2) increased numbers of senescent astrocytes have been identified in the brain of AD patients, we hypothesize that aging-associated oxidative stress leads to the accumulation of senescent cells in the brain, which in turn promote the pathogenesis and progression of AD via exacerbating amyloid beta (Aβ)-induced neurotoxicity and tau pathology. Therefore, pharmacological elimination of senescent cells can be exploited as a new strategy for AD prevention and treatment. There Specific Aims are proposed to test this hypothesis: in Aim 1 we will determine if there is greater cell type-specific senescence burden in AD as compared to healthy aging brains, in Aim 2 we will elucidate the mechanisms by which senescent cells influence AD pathogenesis and progression, and in Aim 3 we will evaluate the therapeutic potential of selective senolytic agents to prevent and mitigate AD progression and cognitive declines. Successful completion of this project will provide novel insights into the mechanisms by which senescent cells affect brain aging and drive the pathogenesis of AD. More importantly, we anticipate that outcomes of this study will substantially facilitate the development of new and more efficacious strategies for AD prevention and treatment.

项目描述 阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是进行性认知、 目前，超过 560 万美国人患有 AD，这个数字。 预计到 2060 年将增加到 1500 万。尽管已经批准了一些临床干预措施 AD 的治疗，不幸的是，它们在改变临床症状方面仅​​表现出有限的效果 相对较短的时间，没有显示出对疾病进展的明显治疗效果。 清楚地了解 AD 发病机制和进展的机制是一个重大障碍 该提案的目标是通过开发创新和有效的疗法来弥补这一差距。 我的实验室和其他人的实验室已经证明了衰老在大脑衰老和 AD 发病机制中的作用。 AD患者大脑中衰老细胞的数量显着增加，并且去除 在临床前动物模型中，衰老细胞可以预防认知能力下降并减轻 AD 病理。 根据证据，结果表明衰老细胞在 AD 发病机制和治疗中发挥着关键作用。 我们和其他人提供的信息是：1) 氧化应激是 AD 的病理特征，2) 在 AD 患者的大脑中发现了衰老的星形胶质细胞，我们捕捉到了与衰老相关的现象 氧化应激导致大脑中衰老细胞的积累，进而促进 AD 的发病机制和进展通过加剧淀粉样蛋白 β (Aβ) 诱导的神经毒性和 tau 蛋白来实现 因此，通过药物消除衰老细胞可以作为一种新的策略。 AD 预防和治疗提出了具体目标来检验这一假设：在目标 1 中，我们将 确定与健康衰老的大脑相比，AD 中是否存在更大的细胞类型特异性衰老负担， 在目标2中，我们将阐明衰老细胞影响AD发病机制和 在目标 3 中，我们将评估选择性 senolytic 药物预防和治疗的治疗潜力 缓解 AD 进展和认知能力下降。该项目的成功完成将提供新颖的见解。 研究衰老细胞影响大脑衰老并驱动 AD 发病机制的机制。 重要的是，我们预计这项研究的结果将极大地促进新的和 更有效的 AD 预防和治疗策略。