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（由适用提供）：拟议的研究的长期目标是了解β-淀粉样蛋白肽（Aß）的疾病与疾病相关的毒性特性，这与阿尔茨海默氏病（AD）的病因强有关。该提议的中心假设是，Aß损害膜的能力有助于阿尔茨海默氏病病理学，而tau高磷酸化是AD病理学的标志，是对膜损伤的神经元反应的结果。我们提出，AD中的神经元细胞死亡是由Aß的低聚形式引起的慢性膜损伤引起的慢性tau磷酸化的结果。我们证明了Aß中的单个住宅取代的支持，该假设可以阻止其透化膜的能力，这也使这种胡椒在各种体外和体内模型中无毒。此外，初步研究表明，暴露于膜形成毒素链球菌素O（SLO）的原发性神经元显示出与暴露于Aß引起的Tau高磷酸化的模式。我们将使用原发性神经元培养物和新型的秀丽隐杆线虫模型来检验这一假设，该模型使我们能够可视化活动物中Aß诱导的膜修复。该模型将使我们能够通过工程信息Aß变体（包括已知的家庭广告突变）来更好地定义有毒Aß物种，并主张它们诱导膜修复的能力。至关重要的是，该模型还将使我们能够通过突变潜在参与膜修复的AD风险基因的蠕虫直系同源物（例如Picalm，BIN1和CTNNA2）来测试膜损伤模型的疾病相关性，并确定是否会改变Aß诱导的膜修复。这些研究将通过使用原发性海马神经元来确认tau磷酸化作为一种​​相关性来完成：鉴定阻断Aß毒性（而不是Aß积累）的化合物受到毒性Aß物种及其作用机理的不确定性的阻碍。据信，不溶性，高磷酸化的tau的沉积被认为是Aß积累的下游结果，但是尚未建立这种情况的生物学原理。我们提出的研究可能为发展AD疗法的发展提供新的潜在客户，并解释除了AD之外，在一系列的Tauopathies中观察到的变化的TAU代谢。