Peptoid Antagonists of the ApoE/ABeta Interaction as a Novel Anti-ABeta Therapy

描述(申请人提供)：淀粉样蛋白(A)肽和载脂蛋白E(ApoE)之间的直接相互作用已被确认为影响Aβ脑清除、其通过血脑屏障(BBB)的运输以及促进Aβ纤化和在中枢神经系统沉积的重要因素。这种相互作用的大小似乎是异构体特异性的，这为apoE4等位基因与散发性阿尔茨海默病(AD)风险增加之间的联系提供了一种解释。K02申请中提出的主要研究假设是，阻止apoE/A？相互作用的治疗剂将有效地改善AD的A？相关病理。我们先前证明，在AD转基因(TG)小鼠中，用模拟ALI上apoE结合部位的合成肽-A？12-28p阻断apoE/A？结合，并针对体内应用和血脑屏障通透性进行修改，可以减少实质和血管A？沉积的负担，并防止记忆障碍(Sadowski等人)。AJP，2004；165：937；Sadowski等人。美国国家科学院院刊，2006年；第103：18787页)。在这项拨款提案中，我们计划开发和表征无毒的类肽化合物，这种化合物将基于A？12-28序列，但将具有更好的治疗效果、血脑屏障渗透率和生物稳定性。我们有初步的数据证明，一些肽类修饰除了对apoE/A？相互作用的抑制作用外，还可能使化合物的p-折叠断裂。我们也有初步数据表明，通过体内反向微透析给药A？12-28P会导致脑间质液(ISF)的A？变化，类似于PDAPP TG小鼠的apoE基因敲除相关变化。我们计划使用体内微透析来表征新开发的肽样载脂蛋白E/A拮抗剂对ISF A代谢的药效学作用。我们还将测试它们对共表达各种人载脂蛋白E亚型的AD TG APP-SW小鼠A？沉积和行为的影响，以预测不同人类载脂蛋白E亚型携带者的治疗反应。为了阐明这一新的治疗方法的全部有益光谱，我们计划进行补充实验，以确定阻断apoE/A‘相互作用对AS BBB外流的影响，A？寡聚体与纤维形成之间的平衡，以及apoE/A’复合体在神经元内的聚集。 相关性：

DESCRIPTION (provided by applicant): The direct Interaction between ¿-amyloid (A¿) peptide and apolipoprotein E (apoE) has been identified as an important factor affecting A¿ brain clearance, its transport across the blood-brain-barrier (BBB), and the promotion of A¿ fibrillization and deposition in the CNS. The magnitude of this interaction appears to be isoform specific, providing one explanation for the linkage between the apoE4 allele and an increased risk of sporadic Alzheimer's disease (AD). The main research hypothesis set forth in this K02 application is that a therapeutic agent preventing the apoE/A¿ interaction will effectively ameliorate A¿ related pathology of AD. We previously demonstrated that blocking apoE/A¿ binding with a synthetic peptide-A¿12-28P that mimics the apoE binding site on Ali and was modified for in vivo application and BBB permeability, reduces the burden of parenchymal and vascular A¿ deposition and prevents memory impairment in AD transgenic (Tg) mice (Sadowski et al. AJP,2004; 165:937; Sadowski et al. PNAS,2006; 103:18787). In this grant proposal, we are planning to develop and characterize non-toxic peptoid compounds, which will be based on the A¿12-28 sequence but will have improved therapeutic efficacy, BBB penetration, and biostability. We have preliminary data to demonstrate that some peptoid modifications may render compounds p-sheet breakers in addition to their inhibitory effect on apoE/A¿ interaction. We also have preliminary data to show that administration of A¿12-28P through reverse in vivo microdialysis results in A¿ changes in the brain interstitial fluid (ISF) akin to that associated with apoE knockout in PDAPP Tg mice. We plan to use in vivo microdialysis to characterize the pharmacodynamic effect of newly developed peptoid apoE/A¿ antagonists on ISF A¿ metabolism. We also shall test their effect on A¿ deposition and behavior in AD Tg APP-Sw mice co-expressing various human apoE isoforms in order to predict the therapeutic response in carriers of the various human apoE isoforms. Complementary experiments designed to determine the effect of blocking the apoE/A¿ interaction on AS BBB efflux, the equilibrium between A¿ oligomers and fibril formation, and intraneuronal accumulation of apoE/A¿ complexes are planned to elucidate the full beneficial spectrum of this novel therapeutic approach. RELEVANCE: