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

阿尔茨海默病(AD)是一种慢性神经退行性疾病，目前困扰着超过620万美国人 由病理性脑老化引起的疾病，是认知功能障碍的最常见原因 在老年人中。对AD启动和进展的驱动因素缺乏全面的了解 是该领域取得进展的关键障碍，也是目前缺乏可行治疗方法的原因之一 选择。病原体正在成为阿尔茨海默病病因的潜在贡献者。神经学表现 各种病原体急性感染后与AD相关的表型已经被很好地记录下来。 反复感染的长期后果没有得到充分的研究，尽管出现了新的流行病学 临床前证据表明，较高的终生感染负担会损害认知，尤其是在 携带阿尔茨海默病遗传风险的生物体。影响细胞代谢的病原体可能代表了与AD相关的一个关键因素 感染加速AD进展的机制。目前尚不清楚的是，1)更高的 终生接触病原体的频率，特别是那些神经元趋向性有限的病原体，可以促进 AD表型，2)高龄如何增强这种风险，以及3)新陈代谢改变的程度， 由于感染，导致了这些影响。反复接触病毒如何影响AD的确定 作为年龄函数的神经病理发育和认知损害是该领域的迫切需要。我们的 初步数据显示，间歇性感染会导致大脑代谢表型改变 微血管内皮细胞(BMVEC)与认知功能减退相关。我们观察到了重要的 与感染小鼠线粒体功能相关的标志物减少。我们将利用一只衰老的小鼠 反复暴露于病毒的模型，以检测血脑屏障代谢途径的变化和 这与认知能力有何关联。目标1将解决反复接触病毒是否会加速与年龄相关的问题 血脑屏障中细胞的线粒体功能障碍，导致AD的进展。目标2将定义如何 电压依赖性阴离子通道1机械改变BMVEC随年龄增长的线粒体功能。目标3， 确定病毒如何影响血脑屏障通透性作为年龄的函数，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 进行性和认知功能。这一项目可能会揭示新的治疗或预防措施 旨在防止阿尔茨海默病进展的目标，为数百万患者及其护理人员带来希望。

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.