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

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.