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

 描述(由申请人提供)：这项拟议研究的长期目标是了解与阿尔茨海默病(AD)病因学密切相关的β-淀粉样多肽(A？)的与疾病相关的毒性特性。这一建议的中心假设是，Aü破坏膜的能力有助于阿尔茨海默病的病理，而tau过度磷酸化是AD病理的一个标志，是神经元对膜损伤的反应的结果。我们认为阿尔茨海默病的神经细胞死亡是由寡聚型A？引起的慢性膜损伤导致的慢性tau磷酸化的结果。这一假说得到了我们的论证的支持，即在各种体外和体内模型中，阻止其通透膜能力的Aü中的单个残基取代也使该肽无毒。此外，初步研究表明，原代神经元暴露于膜孔形成毒素链球菌素O(SLO)时，其tau蛋白过度磷酸化的模式与Aü诱导的非常相似。我们将使用原代神经元培养和一种新的线虫模型来验证这一假设，该模型使我们能够在活体动物中可视化Aü诱导的膜修复。这个模型将使我们能够通过设计信息丰富的Aü变体(包括已知的家族性AD突变)并分析它们诱导膜修复的能力来更好地定义有毒Aü物种。关键的是，这个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(例如，PICALM、BIN1和CTNNA2)的蠕虫同源基因，并确定这是否改变A？诱导的膜修复，来从基因上测试膜损伤模型的疾病相关性。这些研究将通过使用原代海马神经元来补充，以证实tau磷酸化是膜修复的一个组成部分，并确定这一事件发生在修复途径的什么地方。相关性：由于对有毒的Aü物种及其作用机制的不确定性，阻碍了对A？毒性(而不是A？蓄积)化合物的鉴定。阿尔茨海默病中不溶性、过度磷酸化的tau的沉积被认为是Aü积累的下游结果，但为什么会发生这种情况的生物学基础尚未建立。我们提出的研究可能会为AD治疗的发展提供新的线索，并解释除了AD之外，在一系列tauopathy中观察到的tau代谢的改变。

 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.