Targeting the ANG/TIE2 pathway to treat Alzheimer's disease and related dementias

项目摘要 阿尔茨海默病和相关痴呆症（ADRD）的临床试验在治疗阿尔茨海默病和相关痴呆症（ADRD）方面仅取得有限的成功。 痴呆越来越多的证据表明，许多ADRD的主要贡献者是血脑屏障（BBB） 脑血管功能障碍。该提案的总体目标是测试BBB是否 血管生成素/TIE 2（ANG/TIE 2）靶向治疗可预防脑血管损伤和脑血管功能障碍 通路ANG/TIE 2通路是BBB完整性的关键调节因子。血管生成素-1（ANGPT 1）结合受体 TEK酪氨酸激酶（TIE 2），其导致TIE 2磷酸化（磷酸-TIE 2，p-TIE 2）和活化。 活化的p-TIE 2通过增加紧密连接蛋白调节BBB完整性。相反， 血管生成素-2（ANGPT 2）与TIE 2的结合阻止磷酸化和活化，导致BBB完整性降低。 血管内皮蛋白酪氨酸磷酸酶（VE-PTP）阻止TIE 2的磷酸化，从而诱导TIE 2的表达。 炎症诱导的血管通透性。研究表明，靶向ANG/TIE 2通路可改善 肺动脉高压中的血管健康、败血症中的微血管血栓形成和糖尿病 视网膜病变然而，没有研究调查ANG/TIE 2通路和BBB之间的直接联系 抗抑郁药的完整性因此，我们将测试我们的假设，即操纵ANG/TIE 2通路将 在ADRD中保持BBB完整性和脑血管功能。我们将使用新的野生衍生的 WSB.APP/PS1小鼠模型，其产生ADRD的标志，包括实质斑块沉积， 脑淀粉样血管病、神经炎症、神经变性和认知缺陷。在目标1中，我们 检验降低ANGPT 2水平将增加p-TIE 2，加强紧密连接， 稳定血脑屏障，从而防止脑血管损伤。我们将创建WSB.APP/PS1的队列， WSB（无淀粉样蛋白对照）Angpt 2杂合子（Angpt 2 +/-）小鼠，其年龄分别为4岁（斑块发作）和8岁（斑块发作）。 月（显性ADRD表型）。在这些时间点，我们将评估认知、脑血管完整性， 淀粉样蛋白沉积，神经变性和神经炎症，使用一组体内和死后 分析-包括新的空间识别，正电子发射断层扫描/计算机断层扫描（PET/CT）， 血管渗漏、生化和免疫组织化学。在目标2中，我们将检验治疗 使用VE-PTP抑制剂AKB-9778的WSB.APP/PS1小鼠也将增加p-TIE 2并稳定BBB功能。 从而减少ADRD表型。为了测试这一点，我们将遵循由美国国家卫生研究院开发的强大的临床前管道。 迟发性AD模型生物体开发和评价（MODEL-AD）财团。在确定 通过药代动力学建模的给药方案，将对WSB.APP/PS1和WSB对照小鼠给药 使用AKB-9778治疗4至8个月，并使用Aim中描述的相同试验评估表型 1.总的来说，我们的协同遗传学和药理学方法广泛评估了 靶向ANG/TIE 2通路以预防和/或治疗ADRD。

PROJECT SUMMARY Clinical trials for Alzheimer’s disease and related dementias (ADRDs) have had only limited success in treating dementia. Growing evidence suggests that a major contributor to many ADRDs is blood brain barrier (BBB) compromise and cerebrovascular dysfunction. The overarching aim of this proposal is to test whether BBB compromise and cerebrovascular dysfunction can be prevented by targeting the Angiopoietin/TIE2 (ANG/TIE2) pathway. The ANG/TIE2 pathway is a key regulator of BBB integrity. Angiopoietin-1 (ANGPT1) binds the receptor TEK tyrosine kinase (TIE2), which results in TIE2 phosphorylation (phospho-TIE2, p-TIE2) and activation. Activated p-TIE2 modulates BBB integrity through increasing tight junction proteins. Conversely, binding of Angiopoietin-2 (ANGPT2) to TIE2 prevents phosphorylation and activation, resulting in decreased BBB integrity. Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP) prevents phosphorylation of TIE2, thus inducing inflammation-induced vascular permeability. Studies have shown that targeting the ANG/TIE2 pathway improves vascular health in pulmonary arterial hypertension, microvascular thrombus formation in sepsis, and diabetic retinopathy. However, no studies have investigated a direct link between the ANG/TIE2 pathway and BBB integrity in ADRDs. Therefore, we will test our hypothesis that manipulating the ANG/TIE2 pathway will preserve BBB integrity and cerebrovascular function in ADRDs. We will use the novel wild-derived WSB.APP/PS1 mouse model, which develops hallmarks of ADRDs including parenchymal plaque deposition, cerebral amyloid angiopathy, neuroinflammation, neurodegeneration, and cognitive deficits. In Aim 1, we will test the hypothesis that decreasing ANGPT2 levels will increase p-TIE2, strengthen tight junctions, and stabilize the BBB—thereby preventing cerebrovascular damage. We will create cohorts of WSB.APP/PS1 and WSB (no amyloid control) mice heterozygous for Angpt2 (Angpt2+/-), which will age to 4 (plaque onset) and 8 months (overt ADRD phenotypes). At these timepoints, we will assess cognition, cerebrovascular integrity, amyloid deposition, neurodegeneration, and neuroinflammation using a battery of in vivo and postmortem assays—including novel spatial recognition, positron emission tomography/computed tomography (PET/CT), vascular leakage, biochemistry, and immunohistochemistry. In Aim 2, we will test the hypothesis that treating WSB.APP/PS1 mice with the VE-PTP inhibitor AKB-9778 will also increase p-TIE2 and stabilize BBB function— thereby reducing ADRD phenotypes. To test this, we will follow a robust preclinical pipeline developed by the Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortium. After determining the dosing regimen through pharmacokinetic modelling, WSB.APP/PS1 and WSB control mice will be dosed with AKB-9778 from 4 to 8 months, and phenotypes will be assessed using the same assays described in Aim 1. Collectively, our synergistc genetic and pharmacological approach extensively evaluates the potential for targeting the ANG/TIE2 pathway to prevent and/or treat ADRDs.