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 阿尔茨海默氏病（AD）是一种与年龄相关的神经退行性疾病，具有进行性认知， 功能和行为缺陷。目前，超过560万美国人患有广告，这个数字 预计到2060年，预计将增加到1500万。尽管已批准了几项临床干预措施 AD的处理，不幸的是，它们仅在修饰临床症状时表现出适度的影响 在相对较短的时间内，没有显示出对疾病进展的明显热影响。缺乏 清楚地了解驱动AD发病机理和进展的机制是一个显着的障碍 开发创新和有效的疗法。该提议的目的是解决这个差距 定义敏感在脑老化和AD发病机理中的作用。我的实验室和其他实验室表明 AD患者大脑的感觉细胞数量显着增加，并去除 感觉细胞可以预防临床前动物模型中的认知能力下降并衰减AD病理学。这些 结果表明，感觉细胞在AD发病机理和治疗中的关键作用。基于证据 由我们和其他人提供的1）氧化应激是AD的病理特征，2）增加数量 在AD患者的大脑中已经鉴定出感觉星形胶质细胞，我们假设与衰老相关 氧化应激导致脑中感觉细胞的积累，从而促进 通过恶化的淀粉样β（Aβ）诱导的神经毒性和TAU的发病机理和进展 病理。因此，可以将消除感觉细胞的药物消除作为新的策略 预防和治疗。提出了具体的目标来检验这一假设：在AIM 1中，我们将 与健康的衰老大脑相比 在AIM 2中，我们将阐明感觉细胞影响AD发病机理和 进展，在目标3中，我们将评估选择性塞溶性剂的治疗潜力，以预防和 减轻广告的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 进入感觉细胞影响大脑衰老并驱动AD发病机理的机制。更多的 重要的是，我们预计这项研究的结果将基本支持新的发展和 预防和治疗的更有效策略。