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（由申请方提供）：拟议研究的长期目标是了解β-淀粉样肽（AAPs）的疾病相关毒性特性，AAPs与阿尔茨海默病（AD）的病因密切相关。该提议的中心假设是，AAD损伤膜的能力有助于阿尔茨海默病病理学，并且tau过度磷酸化（AD病理学的标志）是神经元对膜损伤的反应的结果。我们认为AD中的神经元细胞死亡是由于低聚形式的Ablation引起的慢性膜损伤导致的慢性tau蛋白磷酸化的结果。这一假设得到了我们的证明的支持，即阻断其透化膜的能力的Ablation中的单个残基取代也使该肽在各种体外和体内模型中无毒。此外，初步研究揭示，暴露于膜孔形成毒素链球菌溶血素O（SLO）的原代神经元显示出与暴露于Ablu诱导的非常相似的tau过度磷酸化模式。我们将使用原代神经元培养和一种新的C. elegans模型，使我们能够在活体动物中可视化Ablation诱导的膜修复。该模型将使我们能够通过工程化提供信息的ApoA变体（包括已知的家族性AD突变）并测定其诱导膜修复的能力来更好地定义有毒ApoA种类。重要的是，该模型还将允许我们通过突变可能参与膜修复的AD风险基因的蠕虫直系同源物（例如，PICALM、BIN 1和CTNNA 2），并确定这是否改变了Ablation诱导的膜修复。这些研究将通过使用原代海马神经元来补充，以确认tau磷酸化作为膜修复的一个组成部分，并确定该事件发生在沿着修复途径的何处。相关性：由于关于有毒的Aesthetics物种及其作用机制的不确定性，阻碍了对阻断Aesthetics毒性（而不是Aesthetics积累）的化合物的鉴定。AD中不溶性、过度磷酸化tau蛋白的沉积被认为是AAF积累的下游结果，但尚未确定为什么会发生这种情况的生物学原理。我们提出的研究可能为开发AD治疗药物提供新的线索，并解释除AD外，在一系列tau蛋白病中观察到的tau代谢改变。