STAT3 activation in astrocytes as a driver of neurovascular dysfunction in Alzheimer's disease and related dementias

星形胶质细胞中 STAT3 的激活是阿尔茨海默病和相关痴呆症神经血管功能障碍的驱动因素

基本信息

批准号：
10785691
负责人：
Ethan Lippmann
金额：
$ 17.02万
依托单位：
VANDERBILT UNIVERSITY
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：
2022-09-19 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10785691
关键词：
3-Dimensional Adopted Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Astrocytes Autopsy Blood Vessels Brain Brain Injuries Cells Cerebrovascular system Coculture Techniques Dementia Disease Endothelial Cells Exhibits Functional disorder Goals Health Homeostasis Human Imaging Techniques Inflammatory Injury Link Microtomy Molecular Morphology Mus Nerve Degeneration Outcome Pathogenicity Phenotype Research Resolution Role STAT3 gene Serine Proteinase Inhibitors Signal Transduction Site Slice Stimulus Stroke Transgenic Mice Trauma Trees Work alpha 1-Antichymotrypsin blood-brain barrier disruption blood-brain barrier function brain endothelial cell brain tissue cell type chymotrypsin chymotrypsin A cohort dementia risk human tissue in vitro Model in vivo neurovascular prospective repaired response single-cell RNA sequencing spatial relationship synergism transcription factor treatment strategy

项目摘要

Project summary Alzheimer’s disease (AD) and related dementias (ADRD) are exacerbated by neurovascular dysfunction. Astrocytes are key contributors to neurovascular health and blood-brain barrier (BBB) function. In response to pathogenic stimuli, astrocytes adopt a “reactive” phenotype generally characterized by morphological changes. Recent research has shown that reactive astrocytes can adopt a diverse spectrum of molecular identities, but the interplay between these different subtypes of reactive astrocytes and the brain vasculature remains unclear. Indeed, some studies have shown that reactive astrocytes negatively influence BBB function, while others have shown that reactive astrocytes are vital to neurovascular repair after injury. Most of these studies have been performed in the context of stroke or physical trauma, and while there are some emerging studies at single-cell resolution on reactive astrocyte states in ADRDs, there is little to no information on how these different states may directly contribute to neurovascular dysfunction. Herein, we propose to investigate how STAT3 activation in astrocytes drives neurovascular dysfunction in ADRDs. In preliminary work, using thin sections from postmortem human brain tissue, we have shown that AD patients have significantly increased numbers of STAT3-activated astrocytes and inflamed blood vessels. In a human in vitro model of astrocytes cocultured with brain endothelial cells, we have shown that inflammatory stimuli activate STAT3 signaling in astrocytes, which leads to BBB disruption, and inhibition of STAT3 activation in astrocytes mitigates these outcomes. Further, using combinations of the human in vitro model, ex vivo mouse cortical slice cultures, and in vivo manipulations, we have shown that alpha 1-antichymotrypsin (ACT)—a STAT3-regulated serine protease inhibitor—contributes directly to neurovascular dysfunction. Moving forward, we will build on these promising results in the following manner. In Aim 1, we will expand our human tissue studies into larger ADRD cohorts and employ advanced imaging techniques to quantify three-dimensional spatial relationships between STAT3-activated astrocytes and sites of vascular damage. In Aim 2, we will inhibit STAT3 signaling in astrocytes within transgenic mouse models of ADRD and evaluate longitudinal alterations to neurovascular dysfunction; these assessments will include single-cell RNA sequencing to characterize molecular changes to endothelial cells along the entire vascular tree. In Aim 3, we will causally link astrocyte-derived ACT to neurovascular dysfunction in transgenic mouse models of ADRD, as well as characterize prospectively synergy between ACT and APOE, which have known connections in AD and dementia risk. Collectively, outcomes from this work will define the mechanistic roles of STAT3-activated astrocytes in neurovascular dysfunction associated with ADRD and identify potential avenues for targeting astrocytes as an ADRD treatment strategy.

项目摘要阿尔茨海默氏病（AD）和相关痴呆症（ADRD）因神经血管功能障碍而加剧。星形胶质细胞是神经血管健康和血脑屏障（BBB）功能的关键因素。响应致病性刺激，星形胶质细胞采用通常以形态变化为特征的“反应性”表型。最近的研究表明，反应性星形胶质细胞可以采用各种分子身份，但这些不同的反应性星形胶质细胞和脑脉管系统之间的相互作用尚不清楚。实际上，一些研究表明，反应性星形胶质细胞对BBB功能产生负面影响，而其他研究则具有表明反应性星形胶质细胞受伤后对神经血管修复至关重要。这些研究大多数是在中风或身体创伤的背景下进行，虽然单细胞有一些新兴的研究关于反应性星形胶质细胞状态的分辨率，几乎没有关于这些不同状态的信息可能直接导致神经血管功能障碍。本文中，我们建议研究STAT3如何激活在星形胶质细胞中驱动ADRD的神经血管功能障碍。在初步工作中，使用来自尸体后人脑组织，我们已经表明，AD患者的数量显着增加 STAT3激活的星形胶质细胞和发炎的血管。在人类体外模型的星形胶质细胞模型中脑内皮细胞，我们已经表明炎症刺激激活了星形胶质细胞中的STAT3信号传导，这些信号传导导致BBB破坏，并抑制星形胶质细胞中的STAT3激活可减轻这些结果。更远，使用人体内模型的组合，离体小鼠皮质切片培养物和体内操作，我们已经表明α1-抗胰蛋白酶蛋白酶（ACT） - STAT3调节的丝氨酸蛋白酶抑制剂 - 贡献者直接到神经血管功能障碍。向前迈进，我们将基于这些承诺的结果方式。在AIM 1中，我们将将人类组织研究扩展到更大的ADRD队oo群，员工高级量化STAT3激活星形胶质细胞和的三维空间关系的成像技术血管损伤部位。在AIM 2中，我们将抑制转基因小鼠模型中星形胶质细胞中的STAT3信号传导 ADRD并评估神经血管功能障碍的纵向改变；这些评估将包括单细胞RNA测序以表征沿整个血管树向内皮细胞的分子变化。在AIM 3中，我们将在转基因小鼠模型中为星形胶质细胞衍生的ACT与神经血管功能障碍联系起来 ADRD的特征以及ACT和Apoe之间的前瞻性协同作用 AD和痴呆症风险的连接。总的来说，这项工作的结果将定义与ADRD相关的神经血管功能障碍的STAT3激活星形胶质细胞并识别潜在的途径用于将星形胶质细胞作为ADRD治疗策略。