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

橄榄油花酚作为一种新的天然产物分子，用于恢复脑血管功能和 CAA小鼠模型的完整性 项目摘要 脑血管功能障碍在脑淀粉样血管病(CAA)和IS的病理中起关键作用 常见于阿尔茨海默病(AD)。针对血脑屏障(BBB)的治疗药物可能是 有益于多种神经退行性疾病，包括AD、CAA和血管性痴呆。来自我们的研究 实验室证明，油黄酚是一种从特级初榨橄榄油中分离出来的天然酚类化合物，是一种 具有抗CAA和AD小鼠模型神经保护作用的新分子。此外，新的 从我们最近建立的具有CAA特征的独特的体外BBB模型中获得的初步数据 显示油花青素，以纠正该CAA-BBB模型的完整性和功能受损。总目标 这个项目的目的是将我们的临床前活体研究和新的体外血脑屏障研究结果联系起来。 用先进的活体成像工具建立模型，重点研究血脑屏障功能，并进行行为学研究 确定油黄素作为一种有前景的治疗血管Aβ病机疾病，如冠状动脉再生障碍性贫血和阿尔茨海默病。 我们的中心假设是油花青醛是一种新的治疗分子，它针对血脑屏障进行预防 和/或治疗血管Aβ的发病机制。我们将通过追求以下具体的方法来验证这一假设 目的：1)观察口服油黄素改善脑血流量的体内疗效 和BBB完整性，减少突触毒性，改善转基因小鼠的学习和记忆缺陷 CAA/AD模型。这一目标将通过以下分目标进行审查：a)确定油性花青素的功能效应 使用一组认知任务进行治疗，b)研究油黄对脑血流和血脑屏障的影响 使用最先进的多光谱光声层析成像系统的渗透性和功能性 (MSOT)，以及c)评估油花对血管和大脑Aβ负荷、突触完整性和 神经发生。目的2)测定口服油黄素的药代动力学和脑内分布 在野生型小鼠身上。一支由多学科研究人员组成的团队，他们在神经学障碍、行为障碍、 AD治疗的测试、分子成像和临床前药物开发都致力于该项目。 这项工作的结果将支持和推动油黄素的治疗开发进入临床试验。

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.