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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' 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

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，淀粉样蛋白β(Aβ)的沉积在非痴呆者中程度较轻 在脑血管周围发现，这种情况被称为脑淀粉样血管病(CAA)。很可能是因为 阿尔茨海默病中CAA的发展，以及随后的神经血管单位(NVU)功能障碍，可能是由于 一条β过关通道。重要的是，所有的Aβ清除途径都涉及Aβ向血管系统的移动 淘汰赛。排列在所有脑血管内的脑血管内皮细胞(EC)是 并负责通过血脑屏障(BBB)维持大脑的动态平衡。 CAA的发展严重影响大脑健康，因为它会导致EC死亡，血脑屏障崩溃， 微量出血，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控影响NVU的其他细胞，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 阿尔茨海默病的神经炎症。我们的初步数据表明EC线粒体是Aβ的重要感受器 损坏。先前的研究表明，线粒体负责炎症的激活。 线粒体危险相关分子模式(MtDAMPs)的释放途径，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的早期表现。 发病机制，提示早期EC(从而，BBB)功能障碍可能推动和延续AD的病理 也是通过引发广泛的神经炎症。在这里，我们将检验β诱导线粒体的假设 线粒体功能(mtROS和MPTP开放)的有害改变导致的脑内皮细胞功能障碍 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 该提案旨在了解脑内皮细胞线粒体健康和生物能量学中变化的作用， 特别关注线粒体ROS和MPTP对Aβ引起的人内皮细胞炎症激活的调控 (目标1；K99：Y1和Y2)。此外，我们想要评估Aβ如何诱导脑内皮细胞炎症介质 通过mtDAMPs的调节，促进神经胶质线粒体的功能障碍和激活，使用人类 IPSC来源的神经胶质细胞培养(Aim 2；K99：Y2和R00：Y1)。最后，使用淀粉样变性的动物模型 在介绍CAA和胶质增生症(TgSwDI)时，我们将检验Aβ诱导内皮细胞mtROS和MPTP的假设 通过使用mtROS清除剂或耗竭治疗动物来调节神经炎症和认知能力下降 他们对主要MPTP调节因子CypD的ECs(Aim 3；R00：Y1-Y3)。拟议的实验将提供一种 血管线粒体在AD和CAA中作为炎症启动者作用的新认识 导致了新的疾病修正治疗策略的发展。