Olive-derived oleocanthal as a novel natural product molecule to restore cerebrovascular function and integrity in a CAA mouse model

橄榄衍生的油橄榄作为一种新型天然产物分子，可恢复 CAA 小鼠模型的脑血管功能和完整性

• 批准号: 9299508
• 负责人: Amal F Khalil Kaddoumi
• 金额: $ 21.95万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299508
• 关键词: Abeta clearance; Address; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Astrocytes; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Carrier Proteins; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Characteristics; Clinical Drug Development; Clinical Trials; Data; Dementia; Deposition; Development; Disease; Drug Kinetics; Elderly; Endothelial Cells; Frequencies; Functional disorder; Future; Goals; Health; Health Care Costs; Image; Imaging Device; Impairment; In Vitro; Inflammatory; Laboratories; Lead; Learning; Libraries; Mediating; Memory; Memory impairment; Modeling; Mus; Natural Products; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Olive oil preparation; Olives - dietary; Oral; Outcome; Pathogenesis; Pathologic; Pathology; Permeability; Pharmacology; Pharmacy Schools; Phenols; Physiology; Play; Preparation; Prevention; Public Health; Reporting; Research Personnel; Role; Synapses; System; Testing; Therapeutic; Toxic effect; Toxicology; Transgenic Mice; Vascular Dementia; Vascular Diseases; Wild Type Mouse; Work; behavior test; behavioral study; brain cell; cerebrovascular; clinical development; cognitive enhancement; cognitive function; cognitive task; cytokine; high throughput screening; improved; in vivo; in vivo imaging; innovation; molecular imaging; mouse model; multidisciplinary; nervous system disorder; neurogenesis; novel; novel therapeutics; optoacoustic tomography; pre-clinical; prevent; protein transport; screening; therapeutic development; therapeutic target; tool

Olive-derived oleocanthal as a novel natural product molecule to restore cerebrovascular function and integrity in a CAA mouse model Project Summary Cerebral vascular dysfunction plays a critical role in the pathology of cerebral amyloid angiopathy (CAA) and is often observed in Alzheimer’s disease (AD). Therapeutics that target the blood-brain barrier (BBB) may be beneficial in multiple neurodegenerative disorders including AD, CAA, and vascular dementia. Studies from our laboratory demonstrated oleocanthal, a natural phenolic compound isolated from extra-virgin olive oil, as a novel molecule with neuroprotective effects against CAA and AD in mouse models. In addition, new preliminary data obtained from our recently developed unique in vitro BBB model with CAA characteristics showed oleocanthal to rectify the compromised integrity and function of this CAA-BBB model. The overall goal of this project is to tie findings obtained from our pre-clinical in vivo studies and from the novel in vitro BBB model with cutting edge in vivo imaging tools focus on studying the BBB function and with behavioral studies to determine oleocanthal as a promising therapeutic for vascular Aβ pathogenesis disorders like CAA and AD. Our central hypothesis is that oleocanthal is a novel therapeutic molecule that targets the BBB for prevention and/or treatment of vascular Aβ pathogenesis. We will test this hypothesis by pursuing the following specific aims: Aim 1) Investigate the in vivo efficacy of orally administered oleocanthal to improve cerebral blood flow and BBB integrity, reduce synaptotoxicity, and improve learning and memory deficits in transgenic mouse model of CAA/AD. This Aim will be examined via the Sub-Aims: a) determine functional effects of oleocanthal treatment using a battery of cognitive tasks, b) investigate oleocanthal effect on cerebral blood flow and BBB permeability and functionality using the new state-of-the art system Multi-Spectral Optoacoustic Tomography (MSOT), and c) evaluate oleocanthal effect on vascular and cerebral Aβ load, synaptic integrity and neurogenesis. Aim 2) Determine the pharmacokinetics and brain distribution of orally administered oleocanthal in wild type mice. A multidisciplinary team of investigators with expertise in neurologic disorders, behavioral testing, molecular imaging and pre-clinical drug development for AD therapeutics are committed to the project. Outcomes of this work will support and advance therapeutic development of oleocanthal toward clinical trials.

橄榄油皮醛作为一种新的恢复脑血管功能的天然产物分子， CAA小鼠模型中的完整性 项目摘要 脑血管功能障碍在脑淀粉样血管病（CAA）的病理学中起关键作用， 阿尔茨海默病（AD）中经常观察到。靶向血脑屏障（BBB）的治疗剂可以是 有益于多种神经退行性疾病，包括AD、CAA和血管性痴呆。我们的研究 实验室证明，从特级初榨橄榄油中分离出的天然酚类化合物oleocanthal 在小鼠模型中对CAA和AD具有神经保护作用的新分子。此外，新 从我们最近开发的具有CAA特征的独特体外BBB模型中获得的初步数据 显示出油膜，以纠正该CAA-BBB模型的受损的完整性和功能。总目标 该项目的目的是将我们的临床前体内研究和新的体外血脑屏障研究结果联系起来， 具有尖端体内成像工具的模型专注于研究BBB功能， 确定oleocanthal作为血管Aβ发病机制疾病如CAA和AD的有前途的治疗。 我们的中心假设是，油珊瑚醛是一种新的治疗分子，其靶向BBB用于预防 和/或治疗血管Aβ发病机制。我们将通过以下具体步骤来检验这一假设： 目的：1）研究口服油珊瑚醛改善脑血流的体内效应 和BBB完整性，降低突触毒性，并改善转基因小鼠的学习和记忆缺陷 CAA/AD模型。将通过以下子目标检查该目标：a）确定油皮醛的功能作用 B）研究油刺对脑血流量和BB B的影响 使用最先进的新系统多光谱光声断层扫描技术 （MSOT），和c）评估油皮对血管和脑Aβ负荷、突触完整性和神经元损伤的影响。 神经发生目的2）测定口服油珊瑚醛的药代动力学和脑组织分布 在野生型小鼠中。一个多学科的研究小组，在神经系统疾病，行为 用于AD治疗的分子检测、分子成像和临床前药物开发致力于该项目。 这项工作的结果将支持和推进油花醛的临床试验治疗开发。