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氏病（AD）中，在较小程度的非痴呆个体中，淀粉样蛋白β（Aβ）的沉积在脑血管周围发现，这种疾病称为脑淀粉样血管病（CAA）。很可能 CAA的发展，因此是神经血管单元（NVU）功能障碍，可能是由于失败而导致的 Aβ清除途径。重要的是，所有Aβ间隙途径都涉及Aβ向脉管系统运动进化。脑血管内皮细胞（EC），所有脑血管都排在所有脑血管大脑并负责通过血脑屏障（BBB）维持脑稳态。 CAA的发展严重影响了大脑健康，因为它导致EC死亡，BBB崩溃，微视角，副Aβ的积累，是AD进展的最早触发因素之一。 EC 功能障碍还会影响NVU的其他细胞，例如星形胶质细胞或小胶质细胞，通过细微调节这些细胞之间的通信机制。因此，CAA介导的EC功能障碍也可能沉淀 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，线粒体是炎症激活的原因通过线粒体危险相关的分子模式（mtdamps）的途径，包括线粒体活性氧（MTROS），由于形成病理线粒体通透性过渡孔（MPTP）。疾病早期显示脑血管功能障碍和炎症发病机理，表明早期EC（以及BBB）功能障碍可能会驱动和永久性AD病理还通过触发宽度神经炎症。在这里，我们将测试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），脑EC的功能障碍这些改变进一步有助于CAA和AD中的神经血管功能障碍和注射。这提案旨在了解改变在脑ec线粒体健康和生物能学中的作用，特别关注MTRO和MPTP的调节，这是由于Aβ引起的人类EC炎症激活（AIM 1; K99：Y1和Y2）。此外，我们想评估Aβ诱导的大脑EC炎症介质如何使用人类的MTDAMP调制有助于神经胶质线粒体功能障碍和激活 IPSC衍生的神经胶质细胞培养物（AIM 2; K99：Y2和R00：Y1）。最后，使用淀粉样变性的动物模型提出CAA和神经胶质（TGSWDI），我们将测试Aβ诱导的内皮MTROS和MPTP的假设通过用MTROS清除剂治疗动物或耗尽动物，介导神经炎症和认知能力下降他们的CYPD EC是主要的MPTP调节器（AIM 3; R00：Y1-Y3）。提出的实验将提供对血管线粒体作为AD和CAA炎症启动的作用的新了解，有可能导致发展新疾病的治疗策略。