Abeta Oligomers and Mechanisms of Neuronal Cell Death in Alzheimer's Disease

Abeta 寡聚物和阿尔茨海默病神经细胞死亡机制

• 批准号: 8968683
• 负责人: Christopher D. Link
• 金额: $ 22.45万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968683
• 关键词: Alzheimer' s Disease; Alzheimer' s disease risk; Amino Acid Substitution; Amyloid beta-Protein; Animals; Biochemical; Biological; Biological Assay; Biological Models; Caenorhabditis elegans; Candidate Disease Gene; Cells; Chronic; Complement; Cysteine; Deposition; Development; Disease; Endocytosis; Engineering; Escherichia coli; Etiology; Event; Exposure to; Genes; Goals; Hippocampus (Brain); In Vitro; Intestines; Ions; Life; Membrane; Metabolism; Modeling; Mutate; Mutation; Neurons; Orthologous Gene; Pathology; Pathway interactions; Pattern; Peptides; Property; Proteins; Publishing; Structure; System; Tauopathies; Testing; Therapeutic; Toxic effect; Toxin; Uncertainty; Variant; Work; abeta accumulation; abeta oligomer; amyloid peptide; base; familial Alzheimer disease; feeding; genetic resource; hyperphosphorylated tau; in vivo; in vivo Model; monomer; neuron loss; novel; novel therapeutic intervention; public health relevance; repaired; response; risk variant; streptolysin O; tau Proteins; tau mutation; tau phosphorylation

 DESCRIPTION (provided by applicant): The long-term goal of the proposed study is to understand the disease-relevant toxic properties of the ß- amyloid peptide (Aß), which is strongly implicated in the etiology of Alzheimer's disease (AD). The central hypothesis of this proposal is that the ability of Aß to damage membranes contributes to Alzheimer's disease pathology, and tau hyperphosphorylation, a hallmark of AD pathology, is a consequence of a neuronal response to membrane damage. We propose that neuronal cell death in AD is a result of chronic tau phosphorylation resulting from chronic membrane damage caused by oligomeric forms of Aß. This hypothesis is supported by our demonstration that single residue substitutions in Aß that block its ability to permeabilize membranes also render this peptide non-toxic in a variety of in vitro and in vivo models. Furthermore, preliminary studies reveal that primary neurons exposed to the membrane pore- forming toxin streptolysin O (SLO) show patterns of tau hyperphosphorylation very similar to that induced by exposure to Aß. We will test this hypothesis using primary neuronal cultures and a novel C. elegans model that enables us to visualize Aß-induced membrane repair in living animals. This model will allow us to better define the toxic Aß species by engineering informative Aß variants (including known familial AD mutations) and assaying their ability to induce membrane repair. Critically, this model will also allow us to genetically test the disease relevance of the membrane damage model by mutating worm orthologs of AD risk genes potentially involved in membrane repair (e.g., PICALM, BIN1, and CTNNA2), and determining if this alters Aß-induced membrane repair. These studies will be complemented by using primary hippocampal neurons to confirm tau phosphorylation as a component of membrane repair, and to determine where along the repair pathway this event occurs. Relevance: Identification of compounds that block Aß toxicity (rather than Aß accumulation) has been hindered by uncertainty regarding the toxic Aß species and its mechanism of action. The deposition of insoluble, hyperphosphorylated tau in AD is believed to be a downstream consequence of Aß accumulation, but the biological rationale for why this occurs has not been established. Our proposed studies can potentially provide new leads for the development of AD therapeutics, as well as explain the altered tau metabolism observed in a range of tauopathies in addition to AD.

 描述（由申请人提供）：拟议研究的长期目标是了解 β-淀粉样肽 (Aß) 与疾病相关的毒性特性，该肽与阿尔茨海默病 (AD) 的病因学有关。该提议的主要内容是，Aß 损伤细胞膜的能力会导致阿尔茨海默病的病理学，而 tau 蛋白过度磷酸化（AD 病理学的一个标志）是 Aß 损伤的结果。我们认为 AD 中的神经元细胞死亡是由 Aß 寡聚体引起的慢性膜损伤导致的慢性 tau 磷酸化的结果，我们证明 Aß 中的单个残基取代会阻止其能力。此外，初步研究表明，暴露于膜成孔毒素链球菌溶血素 O (SLO) 的原代神经元也使该肽在各种体外和体内模型中无毒。显示 tau 过度磷酸化的模式与暴露于 Aß 所诱导的模式非常相似。我们将使用原代神经元培养物和新的线虫模型来测试这一假设，该模型使我们能够在活体动物中可视化 Aß 诱导的膜修复。通过设计信息丰富的 Aß 变异（包括已知的家族性 AD 突变）并分析其诱导膜修复的能力，更好地定义有毒的 Aß 物种。至关重要的是，该模型还允许我们从基因角度测试膜损伤与疾病的相关性。通过突变可能参与膜修复的 AD 风险基因（例如 PICALM、BIN1 和 CTNNA2）的蠕虫直系同源物来建立模型，并确定这是否会改变 Aß 诱导的膜修复。这些研究将通过使用原代海马神经元确认 tau 磷酸化来补充。作为膜修复的一个组成部分，并确定该事件沿着修复途径发生的位置。 相关性：鉴定阻断 Aß 毒性（而不是 Aß）的化合物。 AD 中不溶性过度磷酸化 tau 蛋白的沉积被认为是 Aß 积累的下游结果，但其生物学原理尚未确定。我们提出的研究可能为 AD 疗法的开发提供新的线索，并解释除 AD 之外的一系列 tau 蛋白病中观察到的 tau 代谢改变。