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.

血管紧张素转换酶1（ACE 1）和肾素-血管紧张素系统（RAS）在血管系统中的作用 调节血压（BP），尽管它们也在大脑神经元中表达， 阿尔茨海默病（AD）。我们在ACE 1中发现了一种罕见的蛋白质改变变体R1279 Q， AD在家庭中为了研究ACE 1 R1279 Q的致病机制，我们制作了敲入（KI）小鼠， 表达同源鼠ACE 1变体。ACE 1 KI小鼠脑ACE 1增加，并具有年龄相关性 神经变性、神经炎症、记忆缺陷和海马（HIP）中的异常EEG，而 其他大脑区域如小脑具有抵抗性，表现出选择性神经变性。这些影响是 加速A？病理学和发生在没有血压变化。重要的是，ACE 1 KI介导的HIP 神经退行性变可通过ACE 1抑制剂（ACEi）和血管紧张素II（AngII）受体类型治疗来预防。 1（AT 1 R）阻滞剂（ARB）药物。ACE 1中通过磷酸化ERK的凋亡和AT 1 R信号传导增加 KI大脑。ACE 1在散发性AD脑中也增加，这表明RAS活性升高是AD患者的常见症状。 AD的特点。我们假设ACE 1 R1279 Q通过升高AngII导致AT 1 R信号过度激活， 这导致易感脑区域如HIP中脆弱神经元的神经变性。一个？和其他 “二次打击”可能会加强年龄诱导的ACE 1/RAS信号转导增加，以加速选择性的细胞凋亡。 神经变性然而，ACE 1相关的机制和细胞类型， 神经变性尚不清楚。在本R 01中，我们将测试关于小胶质细胞、微血管 周细胞和ACE 1介导的神经变性中的神经元。除了假设检验，我们还将 基于发现的创新方法。我们将证实在人类AD中鉴定的脑分子变化， 老鼠.在目标1中，我们将确定小胶质细胞的单细胞转录组和磷酸化蛋白质组， ACE 1 KI小鼠有或无A？病理此外，我们将分析ACE 1 KI小鼠，其中AT 1 R基因 在小胶质细胞中被条件性敲除（cKO）。在目标2中，我们将研究单细胞转录组， 磷酸化蛋白质组的ACE 1 KI小鼠的微血管周细胞有或没有A？病理我们还将 确定ACE 1突变是否损害脑血流并导致ACE 1 KI中的血脑屏障渗漏 小鼠此外，我们将分析ACE 1 KI小鼠与周细胞特异性AT 1 R cKO小鼠杂交。在目标3中，我们 将确定ACE 1 KI小鼠神经元的单细胞转录组和磷酸化蛋白质组， 一个？病理学和有或没有用ARB氯沙坦治疗。此外，我们将分析ACE 1 KI小鼠 与神经元特异性AT 1 R cKO小鼠杂交。在目标4中，我们将验证 人AD脑中的ACE 1 KI小鼠。我们希望R 01能为ACE 1/RAS提供机制性的见解- 介导的神经退行性变及其与A？病理学，知识，这将是非常有价值的， AD治疗的发展。