Infectious history as a determinant of age-related inflammation in Alzheimers disease

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Project Summary Alzheimer’s disease (AD) is a complex disease driven by genetic and environmental components, which converge upon inflammation as a common driver. Notably, inflammatory insults to the central nervous system (CNS), such as viral infection, are correlated with AD and other forms of cognitive decline although the mechanisms linking prior neuroinflammatory exposure to later AD development are unclear. Pathogenic infection leads to profound remodeling of tissues that can have long-term effects on the composition of immune cells in tissues including inflammatory and epigenetic states. For example, after infection, memory T cells infiltrate and persist in the brain long-term as tissue-resident memory T (TRM) cells. While TRM cells provide protection against re-infection in tissues, their presence can also lead to dysregulated inflammation. Moreover, the brain resident macrophages, microglia, and astrocytes can be functionally and epigenetically reprogrammed after exposure to infection, leaving the cells poised to produce inflammatory mediators upon re-infection. While protective to re-infection, these poised inflamed states of brain TRM cells and glia may put the brain at risk of potentially elevated and harmful inflammation. Nearly all AD animal research is performed in animals in specific- pathogen free (SPF) conditions, protected from exposure to environmentally-relevant microbes. Therefore, this project aims to develop more physiological AD models by examining how successive viral infections remodel the CNS and brain-resident microglia, astrocytes and TRM cells, to test if this increases brain inflammation and hastens neurodegeneration and AD pathogenesis. To this end, mice genetically predisposed to develop AD-like symptoms will be serially infected with different pathogens over the first half of their lifetime to replicate exposure to multiple pathogens over one’s lifetime. As the mice age, they will be examined for changes in the composition, transcription, epigenome and function of immune cells, glia, and neurons, and look for earlier signs of AD pathology and dementia. This application will test if a history of infection increases age- related inflammation in the CNS, such as Type I and Type II interferons. By defining pathological links between serial infection, chronic inflammation, and brain resident immune cells, these studies will address this gap in knowledge between one’s infection history and age-related inflammation in the brain that supports AD pathogenesis, and define environmental drivers of sporadic AD. Furthermore, these studies will shed light on the role of brain TRM cells and how they regulate the inflammatory tone of the brain. Considering that most cases of AD are sporadic, and it is an irreversible pathology that currently lacks therapies, it is crucial to elucidate more precisely how environmental factors and the immune system are involved in this disease. Thus, the goal of this grant is to develop more physiologically relevant pre-clinical models that can better inform how the immune response and inflammation contribute to AD and neuronal health with age.