Heterogeneity in toxicity of oligomeric amyloid beta and neuronal resilience in Alzheimer disease

阿尔茨海默病中寡聚淀粉样蛋白的毒性和神经元弹性的异质性

• 批准号: 10507090
• 负责人: ANDREW MICHAEL STERN
• 金额: $ 19.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507090
• 关键词: Address; Aducanumab; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Antibodies; Binding; Biochemical; Biochemistry; Brain; Calcium; Cellular biology; Characteristics; Chemistry; Clinical; Clinical Trials; Clinical Trials Design; Cognitive; Collaborations; Cryoelectron Microscopy; Data; Dementia; Development Plans; Disease; Disease model; Doctor of Philosophy; Drug Design; Egtazic Acid; Enzyme-Linked Immunosorbent Assay; Equipment; Excision; Exposure to; Failure; Funding; Future; Generations; Genetic; Genetic Heterogeneity; Genotype; Goals; Grant; Heterogeneity; Hospital Departments; Hospitals; Human; Image; Impaired cognition; In Vitro; Individual Differences; Induced pluripotent stem cell derived neurons; Instruction; Kinetics; Knowledge; Laboratory Research; Lead; Lesion; Mass Spectrum Analysis; Measures; Medical Genetics; Mentors; Mentorship; Metabolism; Microscope; Modeling; Molecular; Molecular Conformation; Molecular Weight; Monoclonal Antibodies; Nerve Degeneration; Neurites; Neurofibrillary Tangles; Neurology; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Persons; Pharmaceutical Preparations; Phenotype; Phosphorylation; Post-Translational Protein Processing; Property; Protein Chemistry; Protein Conformation; Proteins; Publishing; Research; Research Personnel; Resolution; Senile Plaques; Specificity; Structure; Symptoms; Synapses; Testing; Time; Tissues; Toxic effect; Training; Ultracentrifugation; Woman; Work; Writing; abeta accumulation; age related; amyloid pathology; behavioral neurology; brain tissue; career development; chelation; cohort; design; disease-causing mutation; drug development; experience; experimental study; hyperphosphorylated tau; improved; induced pluripotent stem cell; innovation; instructor; live cell imaging; meetings; monomer; multi-electrode arrays; neuron loss; neuropathology; neurotoxic; neurotoxicity; novel; novel therapeutics; oAβ; preference; reduce symptoms; research and development; resilience; response; skills; stem cells; structural biology; success; symposium; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; theories; therapeutic development; tool; β-amyloid burden

PROJECT SUMMARY This proposal presents a five-year research and career development plan for Andrew Stern, MD, PhD, in the molecular basis of Alzheimer disease (AD), the leading cause of age-related cognitive failure worldwide. Dr. Stern is an Instructor in cognitive and behavioral neurology at Brigham and Women’s Hospital (BWH). The “amyloid cascade hypothesis” is the most studied theory of AD pathogenesis, positing that abnormalities in the metabolism of the Aβ peptide lead to the two defining pathologic lesions of AD (amyloid plaques of aggregated Aβ and neurofibrillary tangles of hyperphosphorylated tau), followed by loss of neurons. There are two central problems with this hypothesis: some patients have abundant amyloid plaques but little neuronal and cognitive loss; and clinical trials of antibodies that removed amyloid plaques have largely failed to slow decline. This proposal addresses these problems by beginning two answer two questions: 1) What biochemical and structural characteristics of the most toxic form of Aβ, soluble oligomers (oAβ), confer its toxicity? Novel monoclonal antibodies will be used to test if calcium-associated and low molecular weight oAβ subsets are correlated with tau abnormalities and dementia. CryoEM will allow structural characterization of immunoaffinity purified calcium-associated oAβ. 2) Do genetic differences cause some patients’ neurons to be more susceptible to toxic oAβ, and is oAβ from patients with high tau burden and dementia more toxic than oAβ from patients without? Induced pluripotent stem cell-derived neurons (iNs) and post mortem brain tissue, from patients with high amyloid pathology but varying tau and cognitive impairment will be compared using live cell imaging. An important innovation is to use naturally-occurring, human brain-derived oAβ, which may be more disease-relevant than synthetic oAβ. These experiments will help explain inconsistencies in our models of AD pathogenesis. In the long term, the results may assist clinical trial and drug design. The training goals of this proposal are for Dr. Stern to develop the necessary expertise to establish an independent laboratory researching the molecular pathogenesis of AD under R01 funding. Over the five years, Dr. Stern will acquire specific skills each with the one-on-one mentorship of an expert advisor: Aβ biochemistry (Dr. Selkoe), iN models (Dr. Young-Pearse), protein conformational chemistry and structural biology (Dr. Vos), neuropathology of neurodegeneration (Dr. Feany), and knowledge of AD clinical therapeutic development (Dr. Sperling). Dr. Stern has developed a training plan consisting of one-on-one meetings, in-person courses, and conferences. All mentors and advisors are renowned experts in their fields. Dr. Selkoe (primary mentor) is a leading AD researcher with decades of mentorship experience, including successful K08 awardees. Dr. Young- Pearse (co-mentor) is also a leading AD researcher, particularly in iN models of disease, and an accomplished mentor. The BWH Department of Neurology is committed to supporting Dr. Stern through protected research time (85%) and state-of-the-art facilities and equipment.

项目概要 该提案为安德鲁·斯特恩（Andrew Stern）医学博士、哲学博士提出了五年研究和职业发展计划， 阿尔茨海默病（AD）的分子基础，阿尔茨海默病是全世界与年龄相关的认知障碍的主要原因。 Stern 博士是布莱根妇女医院 (BWH) 的认知和行为神经学讲师。 “淀粉样蛋白级联假说”是 AD 发病机制中研究最多的理论，认为 Aβ 肽代谢异常导致 AD 的两种典型病理病变（淀粉样蛋白 聚集的 Aβ 斑块和过度磷酸化 tau 的神经原纤维缠结），然后是神经元损失。 这个假说有两个核心问题：一些患者有丰富的淀粉样斑块，但很少有淀粉样斑块。 神经元和认知丧失；去除淀粉样蛋白斑块的抗体的临床试验基本上未能成功 缓慢下降。该提案通过开始回答两个问题来解决这些问题：1）什么 毒性最强的 Aβ 形式——可溶性低聚物 (oAβ) 的生化和结构特征，赋予其 毒性？新型单克隆抗体将用于测试钙相关的低分子量 oAβ 是否 亚群与 tau 蛋白异常和痴呆相关。 CryoEM 将允许结构表征 免疫亲和纯化的钙相关 oAβ。 2）遗传差异是否会导致某些患者的神经元发生变化？ 更容易受到有毒 oAβ 的影响，并且来自高 tau 负荷和痴呆患者的 oAβ 的毒性比 来自患者的 oAβ 没有？诱导多能干细胞衍生的神经元（iNs）和死后脑组织， 来自具有高淀粉样蛋白病理学但不同 tau 和认知障碍的患者将使用活体进行比较 细胞成像。一项重要的创新是使用天然存在的、人脑来源的 oAβ，这可能是 比合成的 oAβ 更具有疾病相关性。这些实验将有助于解释我们模型中的不一致之处 AD 发病机制。从长远来看，结果可能有助于临床试验和药物设计。 该提案的培训目标是让斯特恩博士培养必要的专业知识，以建立一个 在 R01 资助下研究 AD 分子发病机制的独立实验室。五年来， 斯特恩博士将在专家顾问的一对一指导下获得特定技能：Aβ生物化学 （Selkoe 博士）、iN 模型（Young-Pearse 博士）、蛋白质构象化学和结构生物学（Vos 博士）、 神经变性的神经病理学（Feany 博士），以及 AD 临床治疗开发的知识（Dr. Feany） 斯珀林）。斯特恩博士制定了一项培训计划，包括一对一会议、面对面课程和 会议。所有导师和顾问都是各自领域的知名专家。 Selkoe 博士（主要导师）是 领先的 AD 研究人员，拥有数十年的指导经验，包括成功的 K08 获奖者。杨博士- Pearse（共同导师）也是一位领先的 AD 研究人员，特别是在 iN 疾病模型方面，并且是一位卓有成就的研究人员 导师。 BWH 神经病学系致力于通过受保护的研究来支持斯特恩博士 时间（85%）和最先进的设施和设备。