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

靶向 ANG/TIE2 通路治疗阿尔茨海默病和相关痴呆症

• 批准号: 10739485
• 负责人: Gareth R Howell
• 金额: $ 48.05万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739485
• 关键词: ANGPT1 gene; APP-PS1; Age; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Amyloid deposition; Angiopoietin-2; Angiopoietins; Apoptosis; Autopsy; Binding; Biochemistry; Biological Assay; Biological Markers; Biological Process; Blood - brain barrier anatomy; Blood Preservation; Blood Vessels; Brain; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Data; Dementia; Deposition; Development; Diabetic Retinopathy; Disease; Dose; Drug Kinetics; Endothelial Cells; Evaluation; Exploratory/Developmental Grant; Extravasation; Female; Genetic; Health; Heterozygote; Immunohistochemistry; Impaired cognition; Inflammation; Ligands; Link; Mus; Nerve Degeneration; Outcome; Outcome Measure; Partner in relationship; Pathway interactions; Permeability; Pharmacodynamics; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Plasma; Play; Positron-Emission Tomography; Preclinical Testing; Prevention; Protein Tyrosine Kinase; Proteins; Publishing; Regimen; Role; Route; Sepsis; Smooth Muscle Myocytes; Symptoms; TEK gene; TIE-2 Receptor; Testing; Therapeutic; Thrombus; Tight Junctions; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; Vascular Permeabilities; Vascular Smooth Muscle; Weibel-Palade Bodies; Work; X-Ray Computed Tomography; aged; blood-brain barrier function; cerebrovascular; cerebrovascular health; cohort; effectiveness evaluation; human disease; improved; in vivo; male; model organism; mouse model; neurofilament; neuroinflammation; neuropathology; novel; pharmacokinetic model; pharmacologic; phosphatase inhibitor; pre-clinical; preservation; prevent; pulmonary arterial hypertension; receptor binding; retina blood vessel structure; retinal damage; spatial memory; success; vascular endothelial protein tyrosine phosphatase

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.

项目总结 阿尔茨海默病和相关痴呆(ADRD)的临床试验在治疗方面只取得了有限的成功 痴呆症。越来越多的证据表明，血脑屏障(BBB)是导致许多ADRDS的主要因素 妥协和脑血管功能障碍。这项建议的主要目的是测试血脑屏障是否 通过靶向血管生成素/TIE2(Ang/TIE2)可以预防妥协和脑血管功能障碍 路径。Ang/TIE2通路是血脑屏障完整性的关键调节因子。血管生成素-1(ANGPT1)结合受体 Tek酪氨酸激酶(TIE2)，导致TIE2磷酸化(磷酸化TIE2，p-TIE2)和激活。 活化的p-TIE2通过增加紧密连接蛋白来调节血脑屏障的完整性。反之，绑定 血管生成素-2(Angiopoietin-2，ANGPT2)与TIE2结合可阻止磷酸化和活化，导致血脑屏障完整性降低。 血管内皮细胞蛋白酪氨酸磷酸酶(VE-PTP)抑制TIE2的磷酸化，从而诱导 炎症诱导的血管通透性。研究表明，靶向Ang/TIE2通路可以改善 血管健康与肺动脉高压、脓毒症和糖尿病的微血管血栓形成 视网膜病变。然而，还没有研究发现Ang/TIE2途径与血脑屏障之间的直接联系 ADRDS中的完整性。因此，我们将检验我们的假设，即操纵Ang/TIE2途径将 在ADRDS中保持血脑屏障完整性和脑血管功能。我们将用野生动物衍生的小说 WSB.APP/PS1小鼠模型，该模型发展了ADRDS的特征，包括实质斑块沉积， 脑淀粉样血管病、神经炎症、神经变性和认知障碍。在目标1中，我们将 验证以下假设：降低ANGPT2水平将增加p-TIE2，加强紧密连接，并 稳定血脑屏障，从而防止脑血管损伤。我们将创建WSB.APP/PS1和 Angpt2(Angpt2+/-)杂合子WSB(无淀粉样蛋白对照)小鼠，年龄分别为4岁(斑块发病)和8岁 月份(显性ADRD表型)。在这些时间点，我们将评估认知，脑血管完整性， 在体内和死后使用一组淀粉样蛋白沉积、神经变性和神经炎症 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，我们将检验治疗的假设 使用VE-PTP抑制剂AKB-9778的WSB.APP/PS1小鼠也会增加p-TIE2，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 迟发性阿尔茨海默病(MODEL-AD)联盟的模式生物开发与评价。在确定之后 通过药代动力学模型、WSB.APP/PS1和WSB对照小鼠给药方案 使用AKB-9778，为期4至8个月，表型将使用AIM中描述的相同分析方法进行评估 1.总的来说，我们的协同遗传和药理学方法广泛评估了 靶向Ang/TIE2通路以预防和/或治疗ADRD。