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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，阻止载脂蛋白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6-淀粉样蛋白（AB）（AD）的病理学（AD）。淀粉样蛋白（AB）级联假设认为，AB肽的积累构成了AD早期发病机理的关键事件。过量的AB聚集到有毒的低聚物中，然后在大脑的实质中以及产生脑淀粉样血管病的血管壁中的沉积物（CAA）。 CMS中AB的AB，并调节其在血脑屏障（BBB）中的清除率。APOE/AB相互作用的幅度似乎是特异性的，为APOE4等位基因之间的连锁和增加的零星AD风险提供了一种解释。我们已经证明，用合成肽-AB 12-28p阻断APOE/AB结合，以模拟AB上的APOE结合位点并被修饰以在体内施用，减少了地板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，PNAS，2006; 103：18787）。相反，抗AB疫苗接种方法仅防止实质AB沉积而不会影响CAA负担。此外，疫苗接种似乎增加了用AB 12-28p治疗的AD TG动物中缺乏血管周围出血的风险。在这项赠款建议中，我们计划开发基于AB 12-28序列的APOE/ AB相互作用的无毒肽类拮抗剂。这些目标是提高治疗功效，BBB渗透和生物稳定性。由于肽仪的固有仿生特征，它们对降解的抵抗力以及易于化学修饰的耐药性，过去已经成功地采用了这种策略来开发许多治疗性有望的化合物。在AD TG模型中将测试选定的肽型化合物，包括表达不同人类APOE同工型的化合物。这样做是为了预测各种人类APOE同工型的载体中的治疗反应。为了确定这种形式的治疗是否可以减少已经存在的AB沉积物，我们将使用经颅两光子显微镜在AD TG小鼠中对AB斑块进行体内成像。尽管阻止APOE/ AB相互作用的主要目标是防止AB Fibrillar组装和沉积，但我们在本应用程序中还研究了这种方法的其他一些潜在好处。因此，我们将确定阻止APOE/ AB相互作用对AB和APOE清除跨BBB的影响，AB低聚物和原纤维形成之间的平衡以及APOE/ AB复合物的神经内神经元积累。该提案的总体目标是使这种新型的治疗方法更接近临床研究并确定铅肽含量化合物，该化合物可以进一步开发用于人类的安全，长期应用