Targeting APOE modulated neurovascular dysfunction

摘要 APOE4是散发性阿尔茨海默病（AD）的最大遗传风险，与其他基因相比， APOE 3此外，APOE4携带者在临床试验中的反应往往不同，有时是负面的。因此 现代科学面临的主要挑战是开发APOE4携带者的治疗策略， 将军该提案的重点是针对以广告为中心的机械流程， APOE4的影响神经血管（NV）功能障碍，包括血脑屏障（BBB）功能障碍， 作为AD进展的关键组成部分出现。虽然APOE通过多因素调节AD风险， 在NV功能障碍的机制中，APOE的作用越来越明显。事实上，我们的初步数据在小说 EFAD转基因小鼠（表达人APOE和5x家族性阿尔茨海默病（FAD）突变） 表明APOE4和FAD诱导雌性小鼠的认知功能障碍和NV渗漏， 月龄，这是因为APOE4诱导的AD风险在女性中更大。因此，我们的总体假设 APOE4赋予了一种有害的NV表型，可以使用靶向治疗来克服。 越来越多的证据支持重新利用抗高血压药物，特别是血管紧张素 受体阻滞剂（ARB）是通过调节NV治疗AD的一种有前途的药物。在前瞻性研究中 ARB与AD的发病率和进展较低相关，ARB可改善AD样 病理学在有限数量的AD相关模型中。然而，ARB的临床相关问题应 在临床前研究中解决，然后再用于AD。一个主要的问题是，没有研究表明， 表达人APOE的AD模型中的ARB。第二个问题是ARB的有益作用是否 是：1）全身血压依赖性，2）直接作用于大脑的全身血压独立性 BBB处的内皮细胞（BEC），3）通过CNS中的靶介导，或组合。鉴于ARB 可能对血管靶和血压外的血管紧张素受体发挥功能作用， 特别是在脑内，重要的是在临床前研究中考虑脑渗透。事实上，虽然 ARB被认为是脑渗透性差的，有证据表明脑活动和治疗活性脑 生物利用度一般来说，解决经常被忽视的问题，大脑的生物利用度和影响， 疗效至关重要，最近tarenflurbil和semagacestat在AD临床试验中的失败突出了这一点， 没有大脑穿透在没有这些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，并有效地终止对有希望的目标的兴趣。我们假设 重新利用或重新设计ARB是一种有吸引力的AD治疗方法， APOE4携带者。在目标1中，将在野生型小鼠中测量和评估ARB的口服药代动力学， 在E4FAD小鼠中的有效剂量。在目标2中，将评估ARB的疗效和药效学活性， 在EFAD小鼠中使用治疗和预防范例评估。

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.