The role of cell death pathways in mediating neuronal loss during the earliest stages of Alzheimer disease

细胞死亡途径在阿尔茨海默病早期阶段介导神经元损失中的作用

• 批准号: 9314950
• 负责人: Panagiotis Theofilas
• 金额: $ 13.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314950
• 关键词: Affect; Aging; Alzheimer' s Disease; American; Amyloid; Animal Disease Models; Apoptosis; Apoptotic; Aspartic Acid; Autopsy; Binding; Biological Markers; Biology; Brain; Brain Diseases; Brain Stem; CASP3 gene; CASP6 gene; Caspase; Cell Culture Techniques; Cell Death; Cell Nucleus; Cells; Cessation of life; Cleaved cell; Clinical; Clinical Trials; Collection; Communities; Dementia; Development; Disease; Disease Progression; Disease model; Economics; Elderly; Environment; Excision; Follow-Up Studies; Funding; Future; Goals; Heat Shock 70kD Protein Binding Protein; Homeostasis; Human; Impaired cognition; Individual; Institutes; Intervention; Length; Link; Maps; Mediating; Memory; Mentors; Mentorship; Mission; Modeling; Molecular Chaperones; Molecular Profiling; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Prevention; Process; Proteolysis; Proteomics; Research; Research Personnel; Resources; Risk Factors; Role; Sampling; Site; Societies; System; Tauopathies; Testing; Toxic effect; Training; Ubiquitin; United States National Institutes of Health; brain tissue; burden of illness; career development; clinical diagnostics; cognitive change; cost; disability; dorsal raphe nucleus; effective therapy; improved; induced pluripotent stem cell; inhibitor/antagonist; innovation; locus ceruleus structure; multicatalytic endopeptidase complex; neuron loss; neuronal survival; new therapeutic target; novel; novel marker; prevent; protein expression; proteostasis; raphe nuclei; research and development; research facility; social; tau Proteins; tau aggregation; tau-1

ABSTRACT The purpose of this K01 proposal is to provide me with the necessary mentored training to become an independent investigator studying the role of cell death pathways that mediate neuronal loss in individuals with Alzheimer's disease (AD). Neuronal death is a key feature of AD and the best correlate of cognitive impairment and dementia, with neurofibrillary tangle (NFT) pathology being the next-best risk factor. It is currently unknown which mechanisms promote neuronal death in early AD or how these are linked to NFTs. Studies in postmortem AD brains have demonstrated the activation of caspase-mediated cell death pathways, as well as disruption of ubiquitin-proteasome (UPS)-mediated proteolysis. The overall objective of this proposal is to study the interplay between caspases, defective UPS-mediated tau proteostasis and NFT pathology in mediating AD neuronal loss in two nuclei of the human brainstem showing the earliest vulnerability to NFTs: the dorsal raphe nucleus (DRN) and locus ceruleus (LC). We will make use of a unique collection of well- characterized human brains across the AD stages, specifically enriched with early AD brain samples, and a human-derived neuronal culture model for follow-up studies on the mechanisms of caspase activation, tau toxicity and cell death. My central hypothesis is that neuronal dysfunction and subsequent death in AD is mediated by an imbalance between caspase-cleaved tau and defective UPS tau clearance. I will test this hypothesis by pursuing the following specific aims: (1) Determine the relationship between caspase activation, caspase-cleaved tau and neuronal death in progressive stages of AD (2) Examine the role of caspases, the UPS and the co-chaperone CHIP (C terminus of the Hsc70-interacting protein) in mediating neuronal death and NFT pathology in progressive stages of AD. (3) Determine the role of caspase activation, the ubiquitin-proteasome system and CHIP in mediating neuronal death and tau pathology to patient-derived neuronal cell culture. This proposal is significant because it will generate a precise map of the interaction between cell death mechanisms and the proteasome system in mediating early neuronal death and NFTs in AD. This proposal is innovative because interventions targeting early cell death pathways in AD will promote the development of novel biomarkers and therapeutic targets. UCSF and the Gladstone Institute are ideal environments for my proposed training as they provide outstanding research facilities, training resources and excellent mentorship readily available within our scientific community. Completion of the proposed research and career development activities will inform the development of an R01 proposal for conducting independent research on the molecular profiles of the active cell death markers in AD using proteomic analyses. Our findings could inform experimental strategies on revised models for preventing AD pathogenesis before the cognitive changes appear, thus decreasing the economic and societal burden that accompanies AD.

摘要 这份K01提案的目的是为我提供必要的指导培训，使我成为 独立研究人员研究细胞死亡途径在调节神经细胞丢失中的作用 阿尔茨海默病(AD)。神经元死亡是阿尔茨海默病的一个关键特征，也是认知损害的最佳相关性 和痴呆症，神经原纤维缠绕(NFT)病理是次要的危险因素。目前还不清楚 哪些机制促进了AD早期的神经元死亡，或者这些机制是如何与NFT联系起来的。研究项目： 死后阿尔茨海默病的大脑已经证明了caspase介导的细胞死亡途径的激活，以及 破坏泛素-蛋白酶体(UPS)介导的蛋白分解。这项提议的总体目标是 半胱氨酸天冬氨酸氨基转移酶、缺陷的UPS介导的tau蛋白平衡与神经纤维母细胞瘤病理的相互作用 调节人类脑干两个核团的AD神经元丢失，显示出对NFTs的最早易感性： 中缝背核(DRN)和蓝斑(LC)。我们将利用独一无二的水井收藏- 表征了AD各个阶段的人类大脑，特别是丰富了早期AD大脑样本，以及 人源性神经元培养模型用于半胱氨酸氨基转移酶激活机制的后续研究 毒性和细胞死亡。我的中心假设是阿尔茨海默病的神经元功能障碍和随后的死亡 由caspase裂解tau和缺陷的UPS tau清除之间的不平衡所介导。我要测试一下这个 通过追求以下具体目标提出假说：(1)确定caspase与 阿尔茨海默病进展期的激活、caspase裂解tau和神经元死亡(2) Caspase、UPS和辅助伴侣芯片(Hsc70相互作用蛋白的C端)在 参与阿尔茨海默病进展期神经元死亡和NFT病理的研究。(三)明确角色定位 Caspase激活、泛素-蛋白酶体系统和芯片在介导神经元死亡和tau中的作用 患者来源的神经细胞培养的病理学。这项建议意义重大，因为它将产生 细胞死亡机制与蛋白酶体系统在早期调节中相互作用的精确图谱 阿尔茨海默病中的神经元死亡和神经纤维瘤。这项提议是创新的，因为针对早期细胞死亡的干预措施 阿尔茨海默病的治疗途径将促进新生物标志物和治疗靶点的发展。加州大学旧金山分校和 Gladstone研究所是我建议的培训的理想环境，因为他们提供出色的研究 设施、培训资源和优秀的指导在我们的科学界随处可得。 完成拟议的研究和职业发展活动将为R01的开发提供信息 建议对阿尔茨海默病活性细胞死亡标志物的分子图谱进行独立研究 使用蛋白质组学分析。我们的发现可能会为实验策略提供参考，修改模型以预防 在认知变化出现之前就发病，从而减轻了经济和社会负担 伴随着AD。