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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease therapeutic Alzheimer&apos 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

项目摘要

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 (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)，尽管它们也在大脑神经元中表达并可能发挥作用我们在 ACE1 中发现了一种罕见的蛋白质改变变异，即 R1279Q，它与阿尔茨海默病 (AD) 相关。为了研究 ACE1 R1279Q 的致病机制，我们制作了敲入 (KI) 小鼠，表达同源小鼠 ACE1 变体的 ACE1 KI 小鼠大脑 ACE1 增加，并且具有年龄相关性。神经退行性变、神经炎症、记忆缺陷和海马 (HIP) 脑电图异常，同时其他大脑区域（如小脑）具有抵抗力，表明这些影响是选择性的神经变性。重要的是，ACE1 KI 介导的 HIP 会加速 A？通过 ACE1 抑制剂 (ACEi) 和血管紧张素 II (AngII) 受体类型治疗可预防神经退行性变 1 (AT1R) 阻断剂 (ARB) 药物在 ACE1 中增加细胞凋亡和通过磷酸化 ERK 的 AT1R 信号传导。 KI 大脑在散发性 AD 大脑中也增加，表明 RAS 活性升高是一种常见现象。我们认为 ACE1 R1279Q 通过升高的 AngII 导致 AT1R 信号过度激活，这会导致 HIP A 等易受影响的大脑区域的神经元发生变性。 “第二次打击”可能会增强年龄引起的 ACE1/RAS 信号传导增强，从而加速选择性然而，ACE1 相关的神经退行性疾病的机制和细胞类型。神经退行性疾病尚不清楚。在本 R01 中，我们将测试有关小胶质细胞、微血管的作用的假设。 ACE1 介导的神经变性中的周细胞和神经元除了假设检验之外，我们还将采取。我们将确认在人类 AD 大脑中发现的分子变化。在目标 1 中，我们将确定小鼠小胶质细胞的单细胞转录组和磷酸化蛋白质组。具有或不具有A?病理学的ACE1 KI小鼠此外，我们将分析其中AT1R基因的ACE1 KI小鼠。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和具有或不具有 A 病理学的 ACE1 KI 小鼠的微血管周细胞的磷酸化蛋白质组。确定 ACE1 突变是否会损害脑血流并导致 ACE1 KI 中的血脑屏障渗漏此外，我们将分析与周细胞特异性 AT1R cKO 小鼠杂交的 ACE1 KI 小鼠。将测定有或没有的 ACE1 KI 小鼠神经元的单细胞转录组和磷酸化蛋白质组 A? 病理学以及是否接受 ARB 氯沙坦治疗此外，我们将分析 ACE1 KI 小鼠。与神经元特异性 AT1R cKO 小鼠杂交在目标 4 中，我们将验证在中发现的分子和通路。人类 AD 大脑中的 ACE1 KI 小鼠我们预计 R01 将为 ACE1/RAS 提供机制见解。介导的神经变性及其与病理学的关系，这些知识对于 AD疗法的发展。