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

ApoE/Aβ 相互作用的类肽拮抗剂作为新型抗 Aβ 疗法

• 批准号: 8509559
• 负责人: MARTIN Joseph SADOWSKI
• 金额: $ 10.8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509559
• 关键词: Abbreviations; Adverse effects; Affect; Agonist; Alleles; Alzheimer' s Disease; Amides; Amino Acid Substitution; Amino Acids; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Applications Grants; Asses; Award; Behavior; Binding; Binding Sites; Biological; Biological Availability; Biomedical Technology; Blood - brain barrier anatomy; Blood Vessels; Brain; Chemistry; Chimera organism; Chronic; Collaborations; Complex; Data; Deposition; Deuterium; Development; Drug Kinetics; Equilibrium; Genes; Half-Life; Human; Hydrogen; In Vitro; Intercellular Fluid; Investigation; Knock-out; Lead; Ligands; Mass Spectrum Analysis; Measurement; Mediating; Memory impairment; Metabolism; Microdialysis; Modification; Mus; N-substituted Glycines; Pathology; Penetration; Peptides; Peptoids; Permeability; Pharmacodynamics; Population; Principal Investigator; Protein Isoforms; Proteins; Research; Resistance; Risk; Serum; Site; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Wild Type Mouse; apolipoprotein E-4; base; behavior test; design; improved; in vivo; inhibitor/antagonist; novel; novel therapeutic intervention; peptide E (adrenal medulla); peptidomimetics; prevent; research study; response; reuptake; synthetic peptide

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:

描述（由申请人提供）：已确定淀粉样蛋白（A）肽和载脂蛋白E（apoE）之间的直接相互作用是影响A脑清除率、其穿过血脑屏障（BBB）的转运以及促进A在CNS中的液化和沉积的重要因素。这种相互作用的大小似乎是亚型特异性的，为apoE 4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。在该K 02申请中提出的主要研究假设是，预防apoE/A？相互作用的治疗剂将有效改善AD的A？相关病理。我们先前证明，用合成肽-A <$12 - 28 P阻断apoE/A <$结合，可降低AD转基因（Tg）小鼠脑实质和血管A <$沉积的负担，并防止记忆障碍，所述合成肽-A <$12 - 28 P模拟Ali上的apoE结合位点，并针对体内应用和BBB渗透性进行了修饰（Sadowski等人AJP，2004; 165：937; Sadowski等人PNAS，2006; 103：18787）。在这项资助提案中，我们计划开发和表征无毒的类肽化合物，这些化合物将基于A 12-28序列，但将具有改善的治疗效果，BBB渗透和生物稳定性。我们有初步的数据表明，除了对apoE/A？相互作用的抑制作用外，一些类肽修饰可能使化合物成为β-折叠断裂剂。我们也有初步的数据表明，通过反向体内微透析给药A12 - 28 P导致脑间质液（ISF）中的A12变化，类似于PDAPP Tg小鼠中apoE敲除相关的变化。我们计划使用体内微透析来表征新开发的类肽apoE/A <$拮抗剂对ISF A <$代谢的药效学作用。我们还将在共表达各种人apoE亚型的AD Tg APP-Sw小鼠中测试它们对A？沉积和行为的影响，以预测各种人apoE亚型携带者的治疗反应。旨在确定阻断apoE/A <$相互作用对AS BBB流出、A <$寡聚体和原纤维形成之间的平衡以及apoE/A <$复合物的神经元内积累的影响的补充实验计划阐明这种新型治疗方法的全部有益范围。 相关性：