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Cerebrovascular mitochondria as mediators of neuroinflammation in Alzheimer's Disease

脑血管线粒体作为阿尔茨海默病神经炎症的介质

基本信息

批准号：
10723580
负责人：
Rebecca Maria Parodi-Rullan
金额：
$ 11.17万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723580
关键词：
Abeta clearance Acceleration Affect Age Age Months Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloidosis Animal Model Animals Astrocytes Behavioral Biochemical Bioenergetics Blood - brain barrier anatomy Blood Vessels Brain CRISPR/Cas technology Cell Culture Techniques Cell Death Cells Cerebral Amyloid Angiopathy Cerebrovascular Disorders Cerebrovascular system Cerebrum Communication Data Deposition Development Disease Disease Progression Endothelial Cells Endothelium Event Failure Functional disorder Gatekeeping Genes Gliosis Health Hemorrhage Homeostasis Human Immunofluorescence Immunologic Impaired cognition Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Link LoxP-flanked allele Maintenance Mediating Mediator Microglia Mitochondria Mitochondrial DNA Mitochondrial Swelling Molecular Movement Mus Nerve Degeneration Neurofibrillary Tangles Neuroglia Neurons Oral Administration Pathogenesis Pathologic Pathology Pathway interactions Pattern Pericytes Permeability Production Reactive Oxygen Species Research Role Rupture Senile Plaques Signal Pathway Superoxides Testing Therapeutic Variant Vascular Diseases Vascular Endothelium abeta accumulation abeta deposition blood-brain barrier permeabilization brain endothelial cell brain health cell injury cerebral microbleeds cerebrovascular cognitive function cyclophilin D effective therapy experimental study extracellular hyperphosphorylated tau in vitro testing in vivo in vivo evaluation induced pluripotent stem cell mitochondrial dysfunction mitochondrial permeability transition pore neuroinflammation neurovascular neurovascular unit non-demented novel novel therapeutic intervention prevent sensor tau Proteins tool vascular inflammation

项目摘要

ABSTRACT In Alzheimer’s Disease (AD), and to a lesser extent in non-demented individuals, deposition of amyloid β (Aβ) is found around cerebral vessels, a condition called Cerebral Amyloid Angiopathy (CAA). It is likely that the development of CAA, and consequently neurovascular unit (NVU) dysfunction, in AD may result from failure of Aβ clearance pathways. Importantly, all Aβ clearance pathways involve movement of Aβ towards the vasculature for elimination. Cerebrovascular endothelial cells (EC), which line all brain vessels, are the gatekeepers of the brain and are responsible for the maintenance of cerebral homeostasis through the blood-brain barrier (BBB). The development of CAA severely impacts brain health since it results in EC death, BBB breakdown, microhemorrhages, parenchymal Aβ accumulation, and is one of the earliest triggers for AD progression. EC dysfunction also affects other cells of the NVU, such as astrocytes or microglia, through finely regulated communication mechanism between these cells. Therefore, CAA-mediated EC dysfunction may also precipitate neuroinflammation in AD. Our preliminary data suggests that EC mitochondria serve as important sensors of Aβ damage. Previous studies have shown that mitochondria are responsible for the activation of inflammatory pathways through the release of mitochondrial danger associated molecular patterns (mtDAMPs), including mitochondrial reactive oxygen species (mtROS), due to formation of the pathological mitochondrial permeability transition pore (mPTP). Both cerebrovascular dysfunction and inflammation are shown early in disease pathogenesis, suggesting that early EC (and thus, BBB) dysfunction may drive and perpetuate AD pathology also by triggering widespread neuroinflammation. Here, we will test the hypothesis that Aβ induces mitochondrial dysfunction in cerebral ECs through deleterious alterations in mitochondria function (mtROS and mPTP opening) and that these alterations further contribute to neurovascular dysfunction and inflammation in CAA and AD. This proposal seeks to understand the role of alterations in cerebral EC mitochondrial health and bioenergetics, specifically focusing on the modulation of mtROS and mPTP, on human EC inflammatory activation due to Aβ (Aim 1; K99: Y1 and Y2). Moreover, we want to assess how Aβ-induced cerebral EC inflammatory mediators contribute to glial mitochondrial dysfunction and activation, through the modulation of mtDAMPs, using a human iPSC-derived glial cell cultures (Aim 2; K99: Y2 and R00: Y1). Finally, using an animal model of amyloidosis presenting CAA and gliosis (TgSwDI), we will test the hypothesis that Aβ-induced endothelial mtROS and mPTP mediate neuroinflammation and cognitive decline, by treating the animals with a mtROS scavenger or depleting their ECs of CypD, the main mPTP regulator (Aim 3; R00: Y1-Y3). The proposed experiments will provide a novel understanding of the role of vascular mitochondria as initiators of inflammation in AD and CAA, potentially resulting in the development of new disease modifying therapeutic strategies.

摘要在阿尔茨海默病（AD）中，以及在较小程度上在非痴呆个体中，淀粉样蛋白β（Aβ）的沉积在脑血管周围发现，这种情况称为脑淀粉样血管病（CAA）。很可能在AD中CAA的发展以及因此神经血管单位（NVU）功能障碍可能是由于 Aβ清除途径。重要的是，所有Aβ清除途径都涉及Aβ向血管系统的移动以供淘汰。脑血管内皮细胞（EC），内衬所有脑血管，是脑血管内皮细胞的守门人。在脑内，通过血脑屏障（BBB）负责维持脑内稳态。 CAA的发展严重影响大脑健康，因为它导致EC死亡，BBB破坏，微血管扩张、实质Aβ蓄积是AD进展的最早触发因素之一。EC 功能障碍还影响NVU的其他细胞，如星形胶质细胞或小胶质细胞，通过精细调节，这些细胞之间的沟通机制。因此，CAA介导的EC功能障碍也可能导致 AD的神经炎症。我们的初步数据表明EC线粒体作为Aβ的重要传感器损害以前的研究表明，线粒体负责激活炎症反应，通过释放线粒体危险相关分子模式（mtDAMP）的途径，包括线粒体活性氧（mtROS），由于病理性线粒体通透性的形成过渡孔（mPTP）。脑血管功能障碍和炎症都在疾病早期表现出来提示早期EC（以及因此BBB）功能障碍可能驱动和延续AD病理也会引发广泛的神经炎症。在这里，我们将测试假设，Aβ诱导线粒体通过线粒体功能的有害改变（mtROS和mPTP开放）导致脑EC功能障碍并且这些改变进一步导致CAA和AD中的神经血管功能障碍和炎症。这该提案旨在了解改变在脑EC线粒体健康和生物能量学中的作用，特别关注线粒体ROS和mPTP的调节，对Aβ引起的人EC炎症激活的影响， (Aim 1; K99：Y1和Y2）。此外，我们还想评估Aβ诱导的脑EC炎症介质通过调节mtDAMPs，使用人类 iPSC衍生的神经胶质细胞培养物（Aim 2; K99：Y2和R 00：Y1）。最后，使用淀粉样变性的动物模型，提出CAA和神经胶质增生（TgSwDI），我们将测试假设，Aβ诱导内皮细胞线粒体ROS和mPTP 介导神经炎症和认知能力下降，通过用mtROS清除剂或消耗它们的CypD（主要mPTP调节剂）的EC（Aim 3; R 00：Y1-Y3）。拟议的实验将提供对血管线粒体作为AD和CAA炎症引发剂的作用的新认识，导致新的疾病修饰治疗策略的发展。