Targeting the apoE/ABeta Interaction as a Novel AD Therapy

将 apoE/Aβ 相互作用作为一种新型 AD 疗法

• 批准号: 8678647
• 负责人: MARTIN Joseph SADOWSKI
• 金额: $ 13.5万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2015-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678647
• 关键词: Abbreviations; Affect; Affinity; Agonist; Alleles; Alzheimer' s Disease; Amino Acid Substitution; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animal Model; Apolipoprotein E; Apolipoproteins B; Applications Grants; Area; Binding; Binding Sites; Biological; Biological Assay; Biomedical Technology; Biomimetics; Blood - brain barrier anatomy; Brain; Cell Culture Techniques; Cerebral Amyloid Angiopathy; Chemicals; Chimera organism; Circular Dichroism; Clinical Research; Collaborations; Complement; Complex; Data; Deposition; Development; Drug Kinetics; Effectiveness; Equilibrium; Event; Field Flow Fractionation; Genes; Goals; Half-Life; Hemorrhage; Human; Image; Ingestion; Knock-out; LDL-Receptor Related Protein 1; Lead; Length; Letters; Ligands; Lipoproteins; Measurement; Mediating; Memory impairment; Microscopy; Modification; Mus; Neurons; Oral; Oral Administration; Outcome Measure; Pathogenesis; Pathology; Patients; Penetration; Peptides; Permeability; Pharmaceutical Chemistry; Prevention; Protein Isoforms; Proteins; Radiolabeled; Resistance; Risk; Serum; Spectroscopy, Fourier Transform Infrared; Structure; Surface Plasmon Resonance; Testing; Therapeutic; Therapeutic Agents; Thioflavin T; Toxic effect; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Transmission Electron Microscopy; Treatment Efficacy; Vaccination; Wild Type Mouse; apolipoprotein E-3; apolipoprotein E-4; base; behavior test; design; gel electrophoresis; gene replacement; improved; in vitro testing; in vivo; inhibitor/antagonist; intravenous administration; light scattering; mouse model; novel; novel therapeutic intervention; peptidomimetics; prevent; radiotracer; receptor; research study; response; reuptake; synthetic peptide; therapeutic development; transgenic model of alzheimer disease; two-photon

DESCRIPTION (provided by applicant): Our main hypothesis is that a therapeutic agent blocking the interaction between apolipoprotein E and B-amyloid will be effective in reducing and preventing 6-amyloid ( AB ) related pathology of Alzheimer's disease (AD).The B-amyloid ( AB ) cascade hypothesis maintains that accumulation of the AB peptide constitutes a critical event in the early pathogenesis of AD. An excess of AB assembles into toxic oligomers and subsequently into deposits in the brain's parenchyma and in walls of vessels producing cerebral amyloid angiopathy (CAA).The direct binding between AB and apolipoprotein E (apoE) has been identified as an important factor promoting the deposition of AB in the CMS and regulating its clearance across the blood-brain-barrier (BBB).The magnitude of apoE/AB interaction appears to be isoform specific, providing one explanation for the linkage between the apoE4 allele and an increased risk of sporadic AD. We have demonstrated that blocking the apoE/AB binding with a synthetic peptide - AB 12-28P, that mimics the apoE binding site on AB and was modified for in vivo application, reduces the burden of parenchynal AB deposits and CAA, as well as preventing memory impairment in AD transgenic (Tg) mice (Sadowski et al. AJP, 2004; 165:937; Sadowski et al., PNAS, 2006; 103:18787). In contrast, anti- AB vaccination approaches prevent only parenchymal AB deposition without affecting the CAA burden. In addition, vaccination appears to increase the risk of perivascular hemorrhages which were absent in AD Tg animals treated with AB 12-28P. In this grant proposal, we are planning to develop non-toxic peptidomimetic antagonists of the apoE/ AB interaction which will be based on the AB 12-28 sequence. The objectives are to improve therapeutic efficacy, BBB penetration, and biostability. Due to the inherent biomimetic character of peptidomimetics, their resistance to degradation, and ease of chemical modification, this strategy has been successfully employed in the past to develop a number of therapeutically promising compounds. Selected peptidomimetic compounds will be tested in AD Tg models including those expressing differing human apoE isoforms. This will be done to predict the therapeutic response in carriers of the various human apoE isoforms. To determine whether this form of therapy can lead to a reduction of already existing AB deposits we will perform in vivo imaging of AB plaques in AD Tg mice using transcranial two-photon microscopy. Although the primary goal of blocking the apoE/ AB interaction is to prevent AB fibrillar assembly and deposition there are also several other potential benefits of this approach which we investigate in this application. Thus, we will determine the effect of blocking the apoE/ AB interaction on AB and apoE clearance across the BBB, the equilibrium between AB oligomers and fibril formation, and intraneuronal accumulation of apoE/ AB complexes. The overall goal of this proposal is to bring this novel therapeutic approach closer to clinical studies and to identify a lead peptidomimetic compound, which could be further developed for safe, long-term application in humans

描述（由申请人提供）：我们的主要假设是，阻断载脂蛋白 E 和 B-淀粉样蛋白之间相互作用的治疗剂将有效减少和预防阿尔茨海默病 (AD) 的 6-淀粉样蛋白 (AB) 相关病理。B-淀粉样蛋白 (AB) 级联假说认为，AB 肽的积累构成 AD 早期发病机制中的关键事件。过量的 AB 组装成有毒低聚物，随后沉积在脑实质和血管壁中，产生脑淀粉样血管病 (CAA)。AB 与载脂蛋白 E (apoE) 之间的直接结合已被确定为促进 AB 在 CMS 中沉积并调节其跨血脑屏障 (BBB) 清除的重要因素。 apoE/AB 相互作用似乎是同种型特异性的，这为 apoE4 等位基因与散发性 AD 风险增加之间的联系提供了一种解释。我们已经证明，用合成肽 - AB 12-28P（模拟 AB 上的 apoE 结合位点并针对体内应用进行了修改）阻断 apoE/AB 结合，可减轻实质 AB 沉积物和 CAA 的负担，并防止 AD 转基因 (Tg) 小鼠的记忆障碍（Sadowski 等人 AJP，2004；165:937；Sadowski 等） 等人，美国国家科学院院刊，2006 年； 103:18787）。相比之下，抗AB疫苗接种方法仅防止实质AB沉积，而不影响CAA负担。此外，疫苗接种似乎会增加血管周围出血的风险，而用 AB 12-28P 治疗的 AD Tg 动物则不存在这种情况。在这项拨款提案中，我们计划开发基于 AB 12-28 序列的 apoE/AB 相互作用的无毒拟肽拮抗剂。目标是提高治疗效果、血脑屏障渗透性和生物稳定性。由于肽模拟物固有的仿生特性、其抗降解性和易于化学修饰，该策略过去已成功用于开发许多有治疗前景的化合物。选定的拟肽化合物将在 AD Tg 模型中进行测试，包括表达不同人类 apoE 亚型的模型。这样做是为了预测各种人类 apoE 亚型携带者的治疗反应。为了确定这种治疗形式是否可以减少现有的 AB 沉积物，我们将使用经颅双光子显微镜对 AD Tg 小鼠中的 AB 斑块进行体内成像。尽管阻断 apoE/AB 相互作用的主要目标是防止 AB 纤维组装和沉积，但我们在本应用中研究了这种方法的其他几个潜在好处。因此，我们将确定阻断 apoE/AB 相互作用对 AB 和 apoE 穿过 BBB 的清除、AB 寡聚物和原纤维形成之间的平衡以及 apoE/AB 复合物在神经元内积累的影响。该提案的总体目标是使这种新颖的治疗方法更接近临床研究，并确定一种先导肽模拟化合物，可以进一步开发该化合物以安全、长期地应用于人类