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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断载脂蛋白E和B-淀粉样蛋白之间的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）相关病理学。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在脑实质和血管壁聚集形成毒性寡聚体，沉积形成脑淀粉样血管病（cerebral amyloid angiopathy，CAA）。AB与载脂蛋白E（apolipoprotein E，apoE）的直接结合是促进AB在CMS中沉积和调节其通过血脑屏障（blood-brain-barrier，BBB）的重要因素。apoE/apoE比值的大小与AB在脑淀粉样血管病（cerebral amyloid angiopathy，CAA）中的表达有关。AB相互作用似乎是亚型特异性的，为apoE 4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- 28 P（其模拟AB上的apoE结合位点并被修饰用于体内应用）阻断apoE/AB结合，降低了实质AB沉积物和CAA的负担，以及预防AD转基因（Tg）小鼠中的记忆损伤（Sadowski等人，AJP，2004; 165：937; Sadowski等人，PNAS，2006; 103：18787）。相反，抗AB疫苗接种方法仅预防实质AB沉积而不影响CAA负荷。此外，疫苗接种似乎增加了血管周围病变的风险，而这在用AB 12- 28 P处理的AD Tg动物中是不存在的。在这项资助计划中，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。目的是提高治疗效果、BBB渗透性和生物稳定性。由于肽模拟物固有的仿生特性、它们对降解的抗性和易于化学修饰，这种策略在过去已成功地用于开发许多有治疗前景的化合物。将在AD Tg模型（包括表达不同人apoE同种型的模型）中测试选定的拟肽化合物。这将用于预测各种人apoE同种型携带者的治疗反应。为了确定这种形式的治疗是否可以导致已经存在的AB沉积物的减少，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。虽然阻断apoE/ AB相互作用的主要目的是防止AB纤维组装和沉积，但我们在本申请中研究的这种方法也有几个其他潜在的好处。因此，我们将确定阻断apoE/ AB相互作用对AB和apoE穿过BBB的清除率、AB寡聚体和原纤维形成之间的平衡以及apoE/ AB复合物的神经元内积累的影响。该提案的总体目标是使这种新的治疗方法更接近临床研究，并确定一种先导肽模拟物化合物，该化合物可以进一步开发用于人类的安全，长期应用