Targeting APOE modulated neurovascular dysfunction

靶向 APOE 调节的神经血管功能障碍

• 批准号: 9315397
• 负责人: Leon Maing Tai
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315397
• 关键词: ABCG2 gene; Address; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Angiotensin Receptor; Antihypertensive Agents; Biological Availability; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Blood drug level result; Brain; Cerebrovascular Circulation; Clinical; Clinical Trials; Cognition; Data; Disease; Disease Progression; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Failure; Female; Follow-Up Studies; Foundations; Functional disorder; Future; Genetic Risk; Goals; Human; Hypertension; Impaired cognition; In Vitro; Incidence; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Modeling; Modernization; Mus; Mutation; Oral; Participant; Pathology; Patients; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Plasma; Population; Prevention; Process; Prodrugs; Prospective Studies; Publishing; Research; Research Design; Risk; Risk Factors; Role; Science; Sodium Fluorescein; Synapses; Systemic blood pressure; Testing; Therapeutic; Time; Transgenic Mice; Water; Wild Type Mouse; brain endothelial cell; cell type; clinically relevant; genetic risk factor; improved; in vivo; interest; neuroinflammation; neurovascular; novel; object recognition; olmesartan; preclinical study; protein expression; receptor expression; sex; targeted treatment; telmisartan

ABSTRACT APOE4 is the greatest genetic risk for sporadic Alzheimer disease (AD), increasing risk up to 12-fold compared to APOE3. Further, APOE4 carriers often respond differently, sometimes negatively, in clinical trials. Thus, a major challenge facing modern science is developing therapeutic strategies for APOE4 carriers, and AD in general. The focus of this proposal is to target mechanistic processes that are AD-centric and further exacerbated by APOE4. Neurovascular (NV) dysfunction, including at the blood-brain barrier (BBB), is emerging as a critical component of AD progression. Although APOE modulates AD risk through multifactorial mechanisms, a role for APOE in NV dysfunction is increasingly evident. Indeed, our preliminary data in novel EFAD transgenic mice (express human APOE and 5xFamilial Alzheimer's disease (FAD) mutations) demonstrates that APOE4 and FAD induce cognitive dysfunction and NV leakiness in female mice by 8 months of age, significant as APOE4-induced AD risk is greater in females. Thus, our overarching hypothesis is that: APOE4 imparts a detrimental NV phenotype which can be overcome using targeted therapeutics. Accumulating evidence supports that repurposing antihypertensive therapeutics, particularly angiotensin receptor blockers (ARBs), is a promising treatment for AD through modulating the NV. In prospective studies ARBs are associated with a lower incidence and progression of AD, and ARBs have improved AD-like pathology in a limited number of AD-relevant models. However, clinically relevant questions for ARBs should be addressed in preclinical studies before repurposing for AD. One major issue is that no studies have tested ARBs in AD models that express human APOE. A second issue centers on whether beneficial effects of ARBs are: 1) systemic blood pressure-dependent, 2) systemic blood pressure-independent by acting directly on brain endothelial cells (BECs) at the BBB, 3) mediated via targets in the CNS, or combinational. Given that ARBs may exert functional effects on angiotensin receptors outside of vascular targets and blood pressure, specifically within the brain, it is important to consider brain penetration in preclinical studies. Indeed, although ARBs are considered poorly brain penetrant there is evidence of brain activity and therapeutically active brain bioavailability. In general, addressing the frequently overlooked issue of brain bioavailability and effects on efficacy is critical, highlighted by the recent failure of tarenflurbil and semagacestat in AD clinical trials, which show zero brain penetration. Proceeding to clinical trials without this information, particularly for drug repurposing, can result in failure and effectively end interest in a promising target. We hypothesize that repurposing or redesigning ARBs is an attractive therapy for AD, and may be particularly efficacious for APOE4 carriers. In Aim 1, the oral pharmacokinetics of ARBs will be measured assessed in wild type mice and in E4FAD mice at efficacious doses. In Aim 2, the efficacy and pharmacodynamics activity of ARBs will be assessed using treatment and prevention paradigms in EFAD mice.

抽象的 APOE4是零星阿尔茨海默氏病（AD）的最大遗传风险，相比之下，风险增加了12倍 到apoe3。此外，在临床试验中，APOE4携带者通常反应不同，有时是负面反应。因此， 现代科学面临的重大挑战是为APOE4运营商制定治疗策略，并在 一般的。该建议的重点是针对以广告为中心的机械过程 APOE4加剧。神经血管（NV）功能障碍，包括血脑屏障（BBB） 作为AD进展的关键组成部分。尽管APOE通过多因素调节AD风险 机制，APOE在NV功能障碍中的作用越来越明显。确实，我们在小说中的初步数据 EFAD转基因小鼠（表达人类ApoE和5xFamilial Alzheimer病（FAD）突变） 证明APOE4和FAD诱导雌性小鼠的认知功能障碍和NV泄漏。 几个月大，在女性中，由于APOE4诱导的AD风险很大。因此，我们的总体假设 就是：APOE4赋予有害的NV表型，可以使用靶向治疗剂克服。 积累的证据支持重新利用降压治疗，尤其是血管紧张素 受体阻滞剂（ARB）是通过调节NV的一种有希望的AD治疗方法。在前瞻性研究中 ARB与AD的发病率和进展较低有关，ARB的AD状态已改善 有限数量的广告含量模型中的病理。但是，关于ARB的临床相关问题应该 在重新利用AD之前，请在临床前研究中解决。一个主要问题是没有研究 表达人类APOE的广告模型中的ARB。第二期的重点是ARB的有益影响 是：1）全身性血压依赖性，2）直接作用于大脑 BBB处的内皮细胞（BEC），3）通过中枢神经系统中的靶标或组合介导。考虑到那个arbs 可能对血管靶靶和血压外的血管紧张素受体产生功能作用， 特别是在大脑中，重要的是在临床前研究中考虑大脑渗透。确实，虽然 ARB认为大脑渗透不良，有大脑活动和治疗活性大脑的证据 生物利用度。通常，解决了脑生物利用度经常被忽视的问题和对 疗效至关重要，这是由于tarenflurbil和Semagacestat在AD临床试验中的最近失败而强调的，这 显示零脑穿透。在没有此信息的情况下进行临床试验，特别是对于药物 重新利用，可能导致失败并有效地结束对有希望的目标的兴趣。我们假设这一点 重新利用或重新设计ARB是广告的有吸引力的疗法，并且可能特别有效 APOE4载体。在AIM 1中，将在野生型小鼠和 在E4FAD小鼠中以有效的剂量。在AIM 2中，ARB的功效和药效学活动将是 使用EFAD小鼠的治疗和预防范例进行评估。