Gut barrier function in Alzheimer’s disease

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The age-related processes that contribute to Alzheimer's disease (AD) development, particularly in the prodromal period, are incompletely understood. Age-related reduction in gut microbiome alpha-diversity is apparent in the majority of older adults, and is suspected of contributing to brain changes, including the development of neurodegenerative disease. Our team published the first comprehensive report describing differences in the gut microbiome observed in AD dementia, including reduced diversity in gut microbiota and altered composition in people with AD dementia compared to age-matched controls. Furthermore, we found that differentially abundant genera were associated with cerebrospinal fluid biomarkers of AD, even among individuals who were cognitively unimpaired. Several studies in mouse models of AD indicate that gut microbiota play a role in the development of AD neuropathology, however to date, the mechanisms underlying these effects are virtually unknown. Recently it has also become clear that the innate immune response in AD plays a critical role in mediating the pathology associated with AD; however the interplay between systemic changes and the innate immune response in AD are not well understood, nor is it known how these factors impact the progression of AD pathology. Our overarching goal is to determine the extent to which alterations in the composition of gut microbiome exacerbate and/or accelerate the development of AD pathology. This proposal is based on the central hypothesis that age-associated gut dysbiosis and inflammation weaken gut barrier function, which in turn leads to the systemic dissemination of microbial components, driving an immune response and system wide changes that worsen AD pathology. To test this hypothesis we propose to study well-characterized participants enrolled in the Wisconsin Alzheimer's Disease Research Center as well as conventional and gnotobiotic APPPS1 mice, to address the following specific aims: 1. Determine the longitudinal relationship between gut microbiome (metagenome), gut inflammation and permeability, and the development of AD pathology in human participants, and 2. Determine the effects of modifying gut permeability on AD pathology in mice. We expect that alterations in gut microbiome composition and gut permeability exacerbate AD pathology in humans, and that impairment of intestinal barrier function and increased gut permeability alters brain homeostasis and exacerbates AD progression in mouse models of AD. Our research group has been working to determine the role of gut microbiome in the development of AD pathology for the past 5 years, and we are perfectly poised to address the proposed aims. We will leverage our expertise in clinical AD, neuroimmunology, and gut microbiology/gnotobiotic mouse models to successfully carry out the proposed project. Completion of the proposed experiments is expected to lead to the development of novel therapeutic strategies for AD and related dementias.