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

• 批准号: 10428585
• 负责人: THOMAS M WISNIEWSKI
• 金额: $ 62.04万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10428585
• 关键词: 3xTg-AD mouse; APP-PS1; Abeta synthesis; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid deposition; Antibodies; Apolipoprotein E; Binding; Biochemical; Biochemistry; Biological; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebral Amyloid Angiopathy; Chimera organism; Cholesterol; Crystallization; Custom; Data Analytics; Databases; Development; Drug Kinetics; Drug Targeting; Ensure; Geometry; Human; Immunotherapy; In Vitro; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; 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; Positron-Emission Tomography; 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; base; behavioral study; design; dosage; experimental study; genetic risk factor; human tissue; improved; in silico; in vivo; in vivo evaluation; inhibitor; innovation; insight; microCT; 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

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 毒性低聚体、淀粉样斑块和脑淀粉样蛋白中A-β多肽的病理性蓄积 血管病变是由于A-β多肽产生增加或清除不足所致。 在阿尔茨海默病(AD)的发病机制中起关键作用。载脂蛋白E4(ApoE4)等位基因是一种主要的遗传基因 晚发性AD的危险因素与淀粉样斑块和血管淀粉样蛋白的增加密切相关 病理学。我们已经证明，用Aβ12-28P肽来阻断apoE/Aβ相互作用构成了一种新的 减少脑实质和血管淀粉样蛋白负荷及tau相关病理学治疗阿尔茨海默病 在多个AD转基因(TG)系中。我们还发现Aβ12-28P可以穿透血脑屏障。 在我们的初步研究中，我们设计了一个来源于Aβ12-28P序列的类肽文库来筛选 与Aβ12-28P相比，APOE/Aβ结合抑制剂具有更高的有效性和安全性。环状类肽通常 与相同或相似序列的线状多肽相比，具有更好的细胞渗透性。事实上，我们的领头羊 多肽CPo_Aβ17-21P是环状的，对apoE4和Aβ的结合具有1.02 nM的KI，并具有 APP/PS1 AD TG模型的治疗效果。我们的初步实验清楚地表明，它是高度 当剂量比亲本Aβ12-28P的剂量低7.5时，有效地减少淀粉样蛋白负荷。 因此，CPO_Aβ17-21P是进一步生化和药物化学的杰出起点 开发新的类肽和类药物小分子。我们建议对我们的铅进行小范围测试，BBB- 穿透性的，类肽分子和类似的类药物，小分子在体内，假设这些将 通过抑制载脂蛋白E4/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组，并将变化与人类组织中的发现相关联(项目1) 和免疫治疗后相同AD TG模型中的蛋白质组(项目3)。我们假设被治疗的人 在apoE4小鼠中，淀粉样蛋白组会转化为更类似apoE3的蛋白质组。 目的1：设计无毒、药代动力学有利的类肽和类药物小分子 ApoE/Aβ相互作用的拮抗剂，并在体外表征它们的作用。 目的2：用3xTg小鼠体内试验铅类和类似药物类小分子， APP/PS1和TgSwDI小鼠与人敲入(Ki)基因APOE2、E3或E4或apoE基因敲除(KO)杂交 背景。 目的3：比较类淀粉样蛋白和类药物小分子中的淀粉样斑块和血管蛋白质组 在Ki APOE2、E3或E4或apoE KO背景下对TG和对照组小鼠进行实验。