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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

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 万美国人由病理性大脑老化引起的疾病，是认知功能障碍的最常见原因老年人缺乏对 AD 发生和进展的驱动因素的全面了解。是该领域取得进展的一个关键障碍，并导致目前缺乏可行的治疗方法病原体正在成为 AD 病因的潜在因素。多种病原体急性感染后与 AD 相关的表型已得到充分记录。尽管流行病学研究不断涌现，但重复感染的长期后果尚未得到充分研究。临床前证据表明，较高的终生感染负担会损害认知能力，尤其是在携带AD遗传风险的生物体影响细胞代谢可能是与AD相关的一个关键因素。感染加速 AD 进展的机制尚不清楚：1）是否更高。终生接触病原体的频率，特别是那些神经元向性有限的病原体，可以促进 AD 表型，2) 高龄如何增加这种风险，以及 3) 新陈代谢改变的程度，由于感染，有助于确定重复的病毒暴露如何影响 AD。神经病理学发展和认知障碍作为年龄的函数是该领域的关键需求。初步数据表明间歇性感染会诱导大脑代谢表型我们观察到微血管内皮细胞（BMVEC）与认知功能下降具有显着相关性。受感染小鼠中与线粒体功能相关的标记物减少我们将利用衰老的小鼠。反复暴露于病毒的模型，以检测血脑屏障中代谢途径的变化，如果反复接触病毒会加速与年龄相关的情况，目标 1 将如何与认知能力相关。血脑屏障细胞的线粒体功能障碍如何导致 AD 进展。电压依赖性阴离子通道 1 随着年龄的增长机械地改变 BMVEC 的线粒体功能。定义了病毒如何影响血脑屏障通透性（作为年龄的函数），从而加速 AD 的进展。这些研究的结果将有助于理解病原体暴露如何影响 AD 该项目可能会揭示新的治疗或预防方法。预防 AD 进展的目标，为数百万患者及其护理人员带来希望。