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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肽作为毒性寡聚体、淀粉样斑块和脑淀粉样蛋白的病理积累血管病（CAA），无论是从Aβ肽的产生增加或从他们的清除不足，是在阿尔茨海默病（AD）的发病机制中至关重要。载脂蛋白E4（apoE 4）等位基因，一个主要的遗传迟发性AD的危险因素，与淀粉样斑块和血管淀粉样蛋白增加密切相关病理我们已经证明，使用Aβ12- 28 P肽阻断apoE/Aβ相互作用构成了一种新的通过减少脑实质和血管淀粉样蛋白负荷以及tau相关病理来治疗AD 在多个AD转基因（Tg）系中。我们还发现Aβ12- 28 P可穿透血脑屏障（BBB）。在我们的初步研究中，我们设计了一个来源于Aβ12 - 28 P序列的类肽文库来筛选Aβ12 - 28 P。与Aβ12- 28 P相比，apoE/Aβ结合抑制剂具有更高的疗效和安全性。环状类肽通常与相同或相似序列的线性肽相比具有更好的细胞渗透性。事实上，我们的领导类肽CPO_Aβ17- 21 P是环状的，对apoE 4和Aβ结合的Ki为1.02 nM，在APP/PS1 AD Tg模型中的治疗功效。我们的初步实验清楚地表明，有效降低淀粉样蛋白负荷，剂量比母体Aβ12- 28 P低7.5倍。因此，CPO_Aβ17- 21 P是进一步生物化学和药物化学的杰出起点新型类肽和类药物小分子的开发。我们建议测试我们的铅小，BBB- 渗透剂、类肽分子和类似的药物样小分子，假设这些将通过抑制apoE 4/Aβ相互作用降低神经元和突触毒性。我们将调查如何这些治疗影响淀粉样蛋白质组，并将变化与人体组织中的发现相关联（项目1）以及免疫治疗后相同AD Tg模型中的蛋白质组（项目3）。我们假设， apoE 4小鼠中的淀粉样蛋白质组将转化为更类似apoE 3的蛋白质组。目的1：设计无毒、药代动力学良好的类肽和类药小分子的apoE/Aβ相互作用的拮抗剂，并在体外表征其作用。目的2：使用3xTg小鼠在体内测试先导类肽和类似药物样小分子， APP/PS1和TgSwDI小鼠与人敲入（KI）apoE 2、E3或E4或apoE敲除（KO）小鼠杂交背景目的3：比较类肽和类药物小分子淀粉样斑块和血管蛋白质组在KI apoE 2、E3或E4或apoE KO背景下治疗Tg小鼠和对照小鼠。