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.

项目摘要 阿尔茨海默氏病和相关痴呆症（ADRD）的临床试验在治疗方面的成功率很高 失智。越来越多的证据表明，许多ADRD的主要贡献是血脑屏障（BBB） 妥协和脑血管功能障碍。该提案的总体目的是测试BBB是否 可以通过靶向Angiopietin/TIE2（ANG/TIE2）来防止妥协和脑血管功能障碍 路径。 ANG/TIE2途径是BBB完整性的关键调节器。 Angiopietin-1（Angpt1）结合接收器 Tek酪氨酸激酶（TIE2）导致TIE2磷酸化（Phosho-Tie2，p-Tie2）和激活。 激活的P-TIE2通过增加紧密连接蛋白来调节BBB的完整性。相反，约束 Angiopietin-2（Angpt2）TIE2可防止磷酸化和激活，从而导致BBB完整性降低。 血管内皮蛋白酪氨酸磷酸酶（VE-PTP）可防止TIE2的磷酸化，从而诱导 炎症引起的血管通透性。研究表明，靶向ANG/TIE2途径有所改善 肺动脉高压，败血症的微血管血栓形成和糖尿病的血管健康 视网膜病。但是，没有研究研究ANG/TIE2途径与BBB之间的直接联系 ADRD的完整性。因此，我们将测试我们的假设，即操纵ANG/TIE2途径将 在ADRDS中保留BBB完整性和脑血管功能。我们将使用小说野生 WSB.App/PS1小鼠模型，发展为ADRD的标志，包括副斑块沉积， 脑淀粉样蛋白血管病，神经炎症，神经变性和认知缺陷。在AIM 1中，我们将 检验以下假设，即降低ANGPT2水平将增加P-TIE2，更紧密的连接和 稳定BBB - 通过防止脑血管损伤。我们将创建wsb.app/ps1和 WSB（无淀粉样蛋白对照）小鼠杂合子的Angpt2（Angpt2 +/-），该小鼠的年龄将老化为4（斑块发作）和8 月份（明显的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，使用体内和验尸电池 测定 - 包括新型空间识别，正电子发射断层扫描/计算机断层扫描（PET/CT）， 血管泄漏，生物化学和免疫组织化学。在AIM 2中，我们将检验以下假设 WSB.APP/PS1具有VE-PTP抑制剂AKB-9778的小鼠也将增加P-TIE2并稳定BBB功能 - 从而减少了ADRD表型。为了测试这一点，我们将遵循由 建模为晚期AD（Model-AD）财团的模型组织开发和评估。确定后 通过药代动力学建模，WSB.APP/PS1和WSB控制小鼠的剂量方案 AKB-9778从4到8个月，将使用AIM中描述的相同评估来评估表型 1。总的来说，我们的协同遗传和药物方法广泛评估了潜力 针对ANG/TIE2途径预防和/或治疗ADRD。