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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.

抽象的在阿尔茨海默病 (AD) 中，以及在较小程度上在非痴呆个体中，β 淀粉样蛋白 (Aβ) 的沉积在脑血管周围发现这种疾病，称为脑淀粉样血管病 (CAA)。这很可能是 AD 中 CAA 的发展以及随后的神经血管单元 (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 向脉管系统的移动用于消除。脑血管内皮细胞 (EC) 排列在所有脑血管中，是大脑的看门人。大脑并负责通过血脑屏障（BBB）维持大脑稳态。 CAA 的发展严重影响大脑健康，因为它会导致 EC 死亡、BBB 崩溃、微出血、实质 Aβ 积聚，是 AD 进展的最早触发因素之一。欧共体功能障碍还会通过精细调节影响 NVU 的其他细胞，例如星形胶质细胞或小胶质细胞这些细胞之间的通讯机制。因此，CAA 介导的 EC 功能障碍也可能导致 AD 中的神经炎症。我们的初步数据表明 EC 线粒体是 Aβ 的重要传感器损害。先前的研究表明线粒体负责炎症的激活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均在疾病早期表现出来发病机制，表明早期 EC（以及 BBB）功能障碍可能驱动并延续 AD 病理还通过引发广泛的神经炎症。在这里，我们将检验 Aβ 诱导线粒体的假设通过线粒体功能的有害改变（mtROS 和 mPTP 开放）导致大脑 EC 功能障碍这些改变进一步导致 CAA 和 AD 的神经血管功能障碍和炎症。这该提案旨在了解大脑 EC 线粒体健康和生物能量学改变的作用，特别关注 mtROS 和 mPTP 的调节，以及 Aβ 引起的人类 EC 炎症激活（目标 1；K99：Y1 和 Y2）。此外，我们想要评估 Aβ 诱导的脑 EC 炎症介质如何通过使用人类的 mtDAMP 调节，导致胶质细胞线粒体功能障碍和激活 iPSC 衍生的神经胶质细胞培养物（目标 2；K99：Y2 和 R00：Y1）。最后，使用淀粉样变性动物模型呈现 CAA 和神经胶质增生 (TgSwDI)，我们将检验 Aβ 诱导的内皮 mtROS 和 mPTP 的假设通过用 mtROS 清除剂或消耗剂治疗动物，介导神经炎症和认知能力下降他们的 ECs CypD，主要的 mPTP 调节器（目标 3；R00：Y1-Y3）。所提出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，可能从而开发出新的疾病改变治疗策略。