Mechanisms of Angiotensin I Converting Enzyme in Alzheimer's disease

血管紧张素I转换酶在阿尔茨海默病中的作用机制

• 批准号: 10568226
• 负责人: ROBERT J VASSAR
• 金额: $ 223.14万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568226
• 关键词: Acceleration; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Apoptosis; Blood - brain barrier anatomy; Blood Pressure; Brain; Brain region; Cells; Cerebellum; Cerebrovascular Circulation; Cessation of life; Cognition; Development; Electroencephalography; Enzymes; Extravasation; Family; Genes; Hippocampus; Human; Impairment; Knock-in; Knock-in Mouse; Knockout Mice; Knowledge; Losartan; Mediating; Memory; Memory impairment; Microglia; Molecular; Mus; Mutation; Nerve Degeneration; Neurons; Pathogenicity; Pathology; Pathway interactions; Peptidyl-Dipeptidase A; Pericytes; Pharmaceutical Preparations; Phosphorylation; Predisposition; Proteins; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Resistance; Role; Signal Transduction; Testing; Variant; Vascular System; age related neurodegeneration; blood pressure regulation; brain cell; cell type; conditional knockout; innovation; insight; neuroinflammation; neuron loss; novel therapeutics; prevent; transcriptome

Angiotensin converting enzyme (ACE1) and the renin-angiotensin system (RAS) function in the vascular system to regulate blood pressure (BP), although they are also expressed in neurons of the brain and may have a role in Alzheimer's disease (AD). We discovered a rare protein-altering variant in ACE1, R1279Q, that is associated with AD in families. To investigate the pathogenic mechanism of ACE1 R1279Q, we made knockin (KI) mice that express the cognate murine ACE1 variant. ACE1 KI mice have increased brain ACE1 and have age-related neurodegeneration, neuroinflammation, memory deficits, and abnormal EEG in the hippocampus (HIP), while other brain regions like cerebellum are resistant, demonstrating selective neurodegeneration. These effects are accelerated by A? pathology and occur in the absence of BP changes. Importantly, ACE1 KI-mediated HIP neurodegeneration is prevented by treatment with ACE1 inhibitor (ACEi) and angiotensin II (AngII) receptor type 1 (AT1R) blocker (ARB) drugs. Apoptosis and AT1R signaling via phosphorylated ERK are increased in ACE1 KI brains. ACE1 is also increased in sporadic AD brain, suggesting that elevated RAS activity is a common feature of AD. We hypothesize that ACE1 R1279Q causes over-activation of AT1R signaling via elevated AngII, which leads to neurodegeneration of vulnerable neurons in susceptible brain regions such as HIP. A? and other “second hits” may potentiate the age-induced increase in ACE1/RAS signaling to accelerate selective neurodegeneration. However, the mechanisms and cell types responsible for ACE1-associated neurodegeneration are unclear. In this R01, we will test hypotheses about the roles of microglia, microvessel pericytes, and neurons in ACE1-mediated neurodegeneration. In addition to hypothesis testing, we will take innovative discovery-based approaches. We will confirm in human AD brain molecular changes identified in mouse. In Aim 1, we will determine the single cell transcriptomes and phosphoproteomes of microglial cells of ACE1 KI mice with or without A? pathology. In addition, we will analyze ACE1 KI mice in which the AT1R gene is conditionally knocked out (cKO) in microglia. In Aim 2, we will investigate the single cell transcriptomes and phosphoproteomes of microvessel pericytes of ACE1 KI mice with or without A? pathology. We will also determine if the ACE1 mutation impairs cerebral blood flow and causes blood-brain barrier leakage in ACE1 KI mice. Additionally, we will analyze ACE1 KI mice crossed with pericyte-specific AT1R cKO mice. In Aim 3, we will determine the single cell transcriptomes and phosphoproteomes of neurons of ACE1 KI mice with or without A? pathology and with or without treatment with the ARB losartan. In addition, we will analyze ACE1 KI mice crossed with neuron-specific AT1R cKO mice. In Aim 4, we will validate molecules and pathways identified in ACE1 KI mice in human AD brain. We expect this R01 will provide mechanistic insights into ACE1/RAS- mediated neurodegeneration and its relationship with A? pathology, knowledge that will be highly valuable for the development of AD therapeutics.

血管紧张素转化酶（ACE1）和肾素 - 血管紧张素系统（RAS）在血管系统中的功能 调节血压（BP），尽管它们在大脑的神经元中也表达 在阿尔茨海默氏病（AD）中。我们在ACE1 R1279Q中发现了一种罕见的改变蛋白质的变体 在家庭中有广告。为了研究ACE1 R1279Q的致病机理，我们使敲击蛋白（Ki）小鼠是 表达同源鼠ACE1变体。 ACE1 ki小鼠的大脑ACE1增加并与年龄相关 神经变性，神经炎症，记忆定义和海马（髋关节）异常的脑电图，而 小脑等其他大脑区域具有抗性，表现出选择性神经退行性。这些效果是 加速A？病理学并在没有BP变化的情况下发生。重要的是，ACE1 KI介导的髋关节 通过用ACE1抑制剂（ACEI）和血管紧张素II（Angii）受体类型治疗神经变性。 1（AT1R）阻滞剂（ARB）药物。 ACE1中通过磷酸化ERK的凋亡和AT1R信号传导增加 Ki Brains。偶发的AD大脑中ACE1也有所增加，这表明RAS活性升高是常见的 广告的功能。我们假设ACE1 R1279Q通过高架ANGII引起AT1R信号的过度激活， 这导致易感性神经元（如髋关节）的神经变性。一个？还有其他 “第二次命中”可能会潜在年龄引起的ACE1/RAS信号的增加以加速选择性 神经变性。但是，负责ACE1相关的机制和细胞类型 神经变性尚不清楚。在此R01中，我们将测试有关小胶质细胞的作用的假设 ACE1介导的神经变性中的周细胞和神经元。除了假设检验，我们还将进行 创新的基于发现的方法。我们将在人类广告脑分子分子变化中确认 老鼠。在AIM 1中，我们将确定小胶质细胞的单细胞转录组和磷酸蛋白质组 ACE1 ki小鼠有或没有A？病理。此外，我们将分析AT1R基因的ACE1 Ki小鼠 有条件地将小胶质细胞淘汰（CKO）。在AIM 2中，我们将研究单细胞转录组和 有或没有A的ACE1 Ki小鼠的微血管周细胞的磷酸蛋白酶？病理。我们也会 确定ACE1突变是否会损害脑血流并导致ACE1 Ki中的血脑屏障泄漏 老鼠。此外，我们将分析与周细胞特异性AT1R CKO小鼠穿越的ACE1 Ki小鼠。在AIM 3中，我们 将确定ACE1 KI小鼠神经元的单细胞转录组和磷酸蛋白质组 一个？病理学以及与ARB Losartan治疗或不进行治疗。此外，我们将分析ACE1 Ki小鼠 与神经特异性AT1R CKO小鼠交叉。在AIM 4中，我们将验证分子和途径 人类广告大脑中的ACE1 ki小鼠。我们希望这种R01将为ACE1/RAS-提供机械见解 - 介导的神经变性及其与A的关系？病理学，知道这对 广告疗法的发展。