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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：
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
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/10428585
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 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

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