The Role of Viral Exposure and Age in Alzheimer's Disease Progression

病毒暴露和年龄在阿尔茨海默病进展中的作用

• 批准号: 10717223
• 负责人: Kevin John Zwezdaryk
• 金额: $ 51.94万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717223
• 关键词: 3xTg-AD mouse; Acceleration; Address; Age; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Amyloid beta-Protein; Amyloid deposition; Apoptosis; Automobile Driving; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Calcium; Caregivers; Cell Reprogramming; Cell Separation; Cells; Cerebrum; Characteristics; Chronic; Clinical; Clinical Trials; Cognitive; Consensus; Cytomegalovirus; Cytomegalovirus Infections; Data; Dependence; Development; Disease Progression; Elderly; Epidemiology; Etiology; Exposure to; Extravasation; Flow Cytometry; Frequencies; Functional disorder; Genetic Risk; Genus Hippocampus; Glycolysis; Herpesviridae; Human; Immunofluorescence Immunologic; Impaired cognition; In Vitro; Inbred BALB C Mice; Individual; Infection; Inflammation; Iron; Life; Link; Lysosomes; Measures; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Mus; Nerve Degeneration; Neurologic Symptoms; Neurons; Onset of illness; Organism; Outcome Study; Output; Oxidative Phosphorylation; Oxidative Stress; Oxidative Stress Induction; PECAM1 gene; Pathologic; Pathway interactions; Patients; Peptides; Permeability; Phenotype; Population; Protein Analysis; Reporting; Risk; Risk Factors; Role; Stress; Superoxides; Supporting Cell; Testing; Tight Junctions; Tropism; Ubiquitination; Viral; Viral Load result; Virus; Virus Diseases; Voltage-Dependent Anion Channel; Western Blotting; Work; acute infection; aging brain; blood-brain barrier permeabilization; brain endothelial cell; cognitive ability; cognitive function; cognitive testing; cytochrome c; disease phenotype; emerging pathogen; experience; experimental study; flexibility; healthy aging; improved; infection burden; inhibitor; metabolic abnormality assessment; metabolic phenotype; metabolic profile; mild cognitive impairment; mitochondrial dysfunction; mitochondrial metabolism; mouse model; neuron loss; neuropathology; novel therapeutic intervention; novel therapeutics; pathogen; pathogen exposure; pre-clinical; preference; prevent; protein expression; release of sequestered calcium ion into cytoplasm; success

Currently afflicting more than 6.2 million Americans, Alzheimer’s Disease (AD) is a chronic neurodegenerative condition that results from pathological brain aging and is the most common cause of cognitive dysfunction among older adults. The lack of comprehensive understanding regarding drivers of AD initiation and progression represents a critical barrier to progress for the field and has contributed to the current lack of viable treatment options. Pathogens are emerging as a potential contributor to the etiology of AD. Neurological manifestations and AD-associated phenotypes following acute infection with a variety of pathogens have been well documented. The long-term consequences of repeated infection are inadequately studied, though emerging epidemiological and preclinical evidence suggests that a higher lifetime infection burden impairs cognition, especially among organisms carrying AD genetic risk. That pathogens impact cellular metabolism may represent a key AD-related mechanism by which infection accelerates AD progression. What remains unknown is 1) whether a higher lifetime exposure frequency to pathogens, especially those that have limited neuronal tropism, can promote an AD phenotype, 2) how advanced age may potentiate this risk, and 3) the extent to which altered metabolism, due to infection, contributes to these effects. Determination of how repeated viral exposure influences AD neuropathological development and cognitive impairment as a function of age is a critical need for the field. Our preliminary data demonstrates that intermittent infection induces altered metabolic phenotypes in brain microvascular endothelial cells (BMVEC) and correlates with reduced cognitive function. We observe significant decreases in markers associated with mitochondrial function in infected mice. We will leverage an aging murine model with repeated exposure to viruses, to detect changes to metabolic pathways in the blood brain barrier and how this correlates to cognitive ability. Aim 1 will address if repeated viral exposure accelerates age-associated mitochondrial dysfunction of cells in the blood brain barrier, contributing to AD progression. Aim 2 will define how voltage dependent anion channel 1 mechanistically alters mitochondrial function in BMVEC with age. Aim 3, defines how viruses impacts blood brain barrier permeability as a function of age, accelerating AD progression. The outcome of these studies will contribute crucial understanding of how pathogen exposure influences AD progression and cognitive function. This project could potentially revealing novel therapeutic or preventative targets to prevent AD progression, offering hope to millions of patients and their caregivers.

目前，阿尔茨海默氏病（AD）遭受了超过620万美国人的痛苦 病理大脑衰老导致的状况，是认知功能障碍的最常见原因 在老年人中。缺乏对广告启动和进步驱动因素的全面理解 代表了该领域进步的关键障碍，并导致目前缺乏可行的治疗 选项。病原体正在成为AD病因的潜在促进者。神经表现形式 与多种病原体急性感染后与广告相关的表型已得到充分证明。 重复感染的长期后果是研究不足的，尽管新兴的流行病学 临床前的证据表明，寿命更高的感染伯宁会损害认知，尤其是在 有遗传风险的生物。病原体会影响细胞代谢可能代表与广告相关的关键 感染加速AD进展的机制。仍然未知的是1）是否更高 病原体的终生暴露频率，尤其是那些有限的神经元热症，可以促进 AD表型，2）年龄有多潜在这种风险，以及3）改变新陈代谢的程度， 由于感染，会导致这些影响。确定重复的病毒暴露如何影响AD 神经病理学的发展和认知障碍随着年龄的影响是对该领域的关键需求。我们的 初步数据表明，间歇性感染会诱导大脑中的代谢表型改变 微血管内皮细胞（BMVEC）与认知功能降低相关。我们观察到了重要的 在感染小鼠中与线粒体功能相关的标记降低。我们将利用老化的鼠 重复接触病毒的模型，以检测血液脑屏障中代谢途径的变化和 这与认知能力如何相关。 AIM 1如果重复的病毒暴露会加速与年龄相关 血液脑屏障中细胞的线粒体功能障碍，导致AD进展。 AIM 2将定义如何 电压依赖性阴离子通道1随着年龄的增长而机械地改变了BMVEC的线粒体功能。目标3， 定义病毒如何影响血脑屏障的渗透性随着年龄的函数，加速AD的进展。 这些研究的结果将有助于对病原体暴露如何影响AD的关键理解 进展和认知功能。该项目可能会揭示新的热或预防性 防止AD进展的目标，为数百万名患者及其护理人员提供了希望。