Blocking the binding of Aβ and apoE as a novel therapeutic approach for AD

阻断 Aβ 和 apoE 的结合作为 AD 的新型治疗方法

基本信息

批准号：
10621848
负责人：
THOMAS M WISNIEWSKI
金额：
$ 51.45万
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：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621848
关键词：
3xTg-AD mouse APP-PS1 Abeta synthesis Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amino Acids Amyloid Amyloid beta-Protein Amyloid deposition Antibodies ApoE knockout mouse Apolipoprotein E Binding Biochemical Biochemistry Biological Blood - brain barrier anatomy Blood Vessels Brain Cells Cerebral Amyloid Angiopathy Chimera organism Cholesterol Custom Data Analytics Databases Development Drug Kinetics Drug Targeting Ensure Geometry Human Immunotherapy In Vitro Knock-in Knock-in Mouse Knock-out Late Onset Alzheimer Disease Lead Libraries Ligand Binding Location Magnetic Resonance Imaging Mediating Mole the mammal Mus Neurons Parents Pathogenesis Pathologic Pathology Pathway interactions Peptides Peptoids Periodicity Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phenylalanine Plasma Process Proteome Proteomics Resistance Safety Senile Plaques Structure Synapses Techniques Testing Toxic effect Transgenic Organisms Treatment Efficacy abeta accumulation aged amyloid pathology antagonist apolipoprotein E-3 apolipoprotein E-4 behavioral study blood-brain barrier penetration data integration design dosage drug-like compound experimental study genetic risk factor human tissue improved in silico in vivo in vivo evaluation inhibitor innovation insight microCT microPET neuroinflammation novel novel strategies novel therapeutic intervention receptor response scaffold screening self assembly small molecule tau Proteins therapeutic effectiveness transgenic model of alzheimer disease treatment effect β-amyloid burden

项目摘要

PROJECT 2- SUMMARY/ABSTRACT The pathological accumulation of Aβ peptides as toxic oligomers, amyloid plaques and cerebral amyloid angiopathy (CAA), either from increased production of Aβ peptides or from their inadequate clearance, is critical in the pathogenesis of Alzheimer’s disease (AD). The apolipoprotein E4 (apoE4) allele, a major genetic risk factor for late-onset AD, was strongly associated with increased amyloid plaque and vascular amyloid pathology. We have shown that using Aβ12-28P peptides to block the apoE/Aβ interaction constitutes a novel treatment for AD by reducing brain parenchymal and vascular amyloid burden as well as tau -related pathology in multiple AD transgenic (Tg) lines. We also showed that Aβ12-28P penetrates the blood-brain-barrier (BBB). In our preliminary studies, we designed a peptoid library derived from the Aβ12 -28P sequence to screen for apoE/Aβ binding inhibitors with higher efficacy and safety compared to Aβ12-28P. Cyclic peptoids typically have better cell permeability compared to the linear peptides of the same or similar sequence. Indeed, our lead peptoid CPO_Aβ17-21P is cyclic, has a Ki of 1.02 nM against the binding of apoE4 and Aβ, and has therapeutic efficacy in an APP/PS1 AD Tg model. Our preliminary experiments clearly show it is highly effective at reducing the amyloid burden at a dosage 7.5-fold lower than that used with the parent Aβ12-28P. CPO_Aβ17-21P is therefore an outstanding starting point for further biochemical and medicinal chemistry development of both novel peptoid and drug-like, small molecules. We propose testing our lead small, BBB- penetrant, peptoid molecule and analogous drug-like, small molecules in vivo, hypothesizing that these will reduce both neuronal and synaptic toxicity by inhibiting the apoE4/Aβ interaction. We will investigate how these treatments affect the amyloid proteome, and correlate changes to findings in human tissue ( Project 1) and the proteome in the same AD Tg models after immunotherapy (Project 3). We hypothesize that the treated amyloid proteome in apoE4 mice will convert to a more apoE3-like proteome. Aim 1: Design non-toxic, pharmacokinetically favorable peptoid and drug-like, small molecule antagonists of the apoE/Aβ interaction, and characterize their effects in vitro. Aim 2: Te st the lead peptoid and analogous drug -like, small molecules in vivo using 3xTg mice, APP/PS1 and TgSwDI mice crossed onto human knock-in (KI) apoE2, E3 or E4, or apoE knock-out (KO) backgrounds. Aim 3: Compare the amyloid plaque and vessel proteomes in peptoid and drug-like, small molecule tre ated Tg and control mice on KI apoE2, E3 or E4, or apoE KO backgrounds .

项目2-摘要/摘要 Aβ肽作为有毒寡聚，淀粉样蛋白斑和脑淀粉样蛋白的病理积累血管病（CAA）是来自AβPepperides的产生或清除不足的产生，是阿尔茨海默氏病（AD）的发病机理至关重要。载脂蛋白E4（APOE4）等位基因，一种主要遗传晚发广告的危险因素与淀粉样菌斑和血管淀粉样蛋白的增加密切相关病理。我们已经表明，使用Aβ12-28PPepperides阻断APOE/Aβ相互作用构成了一种新颖的通过减少脑实质和血管淀粉样burn以及与TAU相关的病理来治疗AD的治疗在多个AD转基因（TG）线中。我们还表明，Aβ12-28P穿透了血脑屏障（BBB）。在我们的初步研究中，我们设计了一个源自Aβ12-28p序列的肽文库，以筛选与Aβ12-28P相比，APOE/Aβ结合抑制剂具有更高的效率和安全性。通常是环状肽与相同或相似序列的线性辣椒相比，具有更好的细胞通透性。确实，我们的领导肽CPO_Aβ17-21P是循环的，针对APOE4和Aβ的结合，Ki为1.02 nm，并且具有 App/PS1 AD TG模型中的治疗效率。我们的初步实验清楚地表明它是高度的在剂量下降低淀粉样蛋白燃烧的剂量比亲本Aβ12-28p低7.5倍的淀粉样剂量燃烧有效。因此，CPO_Aβ17-21P是进一步生化和医学化学的出色起点新型肽和类似药物的小分子的发展。我们建议测试我们的铅大小的BBB- 渗透剂，胡椒分子和类似药物的小分子体内，假设这些将会通过抑制APOE4/Aβ相互作用来降低神经元和突触毒性。我们将调查如何这些疗法影响淀粉样蛋白蛋白质组，并将变化与人体组织的发现相关（项目1）以及免疫疗法后相同AD TG模型中的蛋白质组（项目3）。我们假设接受治疗 APOE4小鼠中的淀粉样蛋白蛋白质组将转换为更apoE3样蛋白质组。 AIM 1：设计无毒的，药代在有利的肽和类似药物的小分子 APOE/Aβ相互作用的拮抗剂，并在体外表征其作用。目标2：使用3xtg小鼠体内的铅肽和类似药物，类似于小分子 App/PS1和TGSWDI小鼠交叉到人敲入（Ki）APOE2，E3或E4或APOE敲除（KO）上背景。 AIM 3：比较胡椒和类似药物的小分子中的淀粉样斑块和血管蛋白质组织在KI APOE2，E3或E4或APOE KO背景上处理的TG和对照小鼠。