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

项目总结 这份提案提出了安德鲁·斯特恩医学博士、博士、 在阿尔茨海默病(AD)的分子基础上，阿尔茨海默病是全球与年龄相关的认知障碍的主要原因。 斯特恩博士是布里格姆妇女医院(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学说，认为 Aβ多肽代谢异常导致AD(淀粉样蛋白)的两种典型病理损害 聚集的Aβ的斑块和过度磷酸化的tau的神经纤维缠结)，随后是神经元的丢失。 这一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 神经元和认知丧失；消除淀粉样斑块的抗体的临床试验在很大程度上失败了 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 Aβ的毒性最强的形式--可溶性低聚物(OAβ)的生化和结构特征赋予其 毒性？新的单抗将用于测试钙相关和低分子质量的OAβ 亚群与tau异常和痴呆症相关。CryoEM将允许对 免疫亲和纯化的钙相关骨性关节炎β。2)遗传差异是否会导致某些患者的神经元 更容易受到有毒的OAβ的影响，来自高tau负荷和痴呆症患者的OAβ比 来自没有？的患者的β？诱导的多能干细胞来源的神经元(INS)和死后脑组织， 来自高度淀粉样变性但不同tau和认知障碍的患者的数据将使用LIVE进行比较 细胞成像。一项重要的创新是使用自然产生的、人脑衍生的OAβ，这可能是 与合成的OAβ相比，与疾病更相关。这些实验将有助于解释我们模型中的不一致之处。 阿尔茨海默病的发病机制。从长远来看，这一结果可能有助于临床试验和药物设计。 这项提议的培训目标是让斯特恩博士发展必要的专业知识，以建立 在R01资助下，独立实验室研究AD的分子发病机制。在过去的五年里， 斯特恩博士将在一位专家顾问的一对一指导下获得各自的特定技能：β生物化学 (Selkoe博士)，在模型中(Young-Pearse博士)，蛋白质构象化学和结构生物学(Vos博士)， 神经退行性变的神经病理学(费尼博士)和AD临床治疗发展的知识(费尼博士)。 斯珀林)。斯特恩博士制定了一项培训计划，包括一对一的会议、面对面的课程和 会议。所有的导师和顾问都是各自领域的知名专家。塞尔科博士(主要导师)是一位 具有数十年指导经验的领先AD研究人员，包括成功的K08奖获得者。杨博士- 皮尔斯(共同导师)也是AD的主要研究人员，特别是在疾病模型方面，也是一位有成就的 门托。BWH神经科致力于通过保护性研究支持斯特恩博士 时间(85%)和最先进的设施和设备。

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.