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:
- 金额:$ 223.14万
- 依托单位:
- 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:
- 关键词:AccelerationAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAngiotensin IIAngiotensin II Type 1 Receptor BlockersAngiotensin-Converting Enzyme InhibitorsApoptosisBlood - brain barrier anatomyBlood PressureBrainBrain regionCellsCerebellumCerebrovascular CirculationCessation of lifeCognitionDevelopmentElectroencephalographyEnzymesExtravasationFamilyGenesHippocampusHumanImpairmentKnock-inKnock-in MouseKnockout MiceKnowledgeLosartanMediatingMemoryMemory impairmentMicrogliaMolecularMusMutationNerve DegenerationNeuronsPathogenicityPathologyPathway interactionsPeptidyl-Dipeptidase APericytesPharmaceutical PreparationsPhosphorylationPredispositionProteinsReceptor, Angiotensin, Type 1Renin-Angiotensin SystemResistanceRoleSignal TransductionTestingVariantVascular Systemage related neurodegenerationblood pressure regulationbrain cellcell typeconditional knockoutinnovationinsightneuroinflammationneuron lossnovel therapeuticspreventtranscriptome
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。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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ROBERT J VASSAR其他文献
ROBERT J VASSAR的其他文献
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{{ truncateString('ROBERT J VASSAR', 18)}}的其他基金
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
- 批准号:
10469445 - 财政年份:2021
- 资助金额:
$ 223.14万 - 项目类别:
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
- 批准号:
10264367 - 财政年份:2021
- 资助金额:
$ 223.14万 - 项目类别:
NORTHWESTERN Alzheimer's Disease Research Center
西北阿尔茨海默病研究中心
- 批准号:
10662473 - 财政年份:2021
- 资助金额:
$ 223.14万 - 项目类别:
Northwestern ADRC Non competing supplement application
西北 ADRC 非竞争性补充申请
- 批准号:
10577047 - 财政年份:2021
- 资助金额:
$ 223.14万 - 项目类别:
The Role of RNA Binding Protein Networks in Tauopathy and Related Dementia
RNA 结合蛋白网络在 Tau 病和相关痴呆中的作用
- 批准号:
10034785 - 财政年份:2020
- 资助金额:
$ 223.14万 - 项目类别:
2nd Kloster Seeon Meeting on BACE Proteases in Health and Disease
关于 BACE 蛋白酶在健康和疾病中的作用的第二届 Kloster Seeon 会议
- 批准号:
9195559 - 财政年份:2016
- 资助金额:
$ 223.14万 - 项目类别:
Molecular Neuropathology and Mechanisms of BACE1 Elevation in Alzheimer's Disease
阿尔茨海默氏病 BACE1 升高的分子神经病理学和机制
- 批准号:
7248235 - 财政年份:2007
- 资助金额:
$ 223.14万 - 项目类别:
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