Role of IgA-biome in intestinal dysbiosis and brain changes in Alzheimer's disease

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Summary An estimated 6.2 million individuals have Alzheimer’s disease (AD) in the US, which is projected to nearly triple by 2050. Although genetic and several environmental factors help explain the etiology of AD, emerging reports recognize significant associations between altered diversity, abundance, and composition of the intestinal microbiota, intestinal dysfunction, loss of epithelial barrier integrity, and the progression of AD. However, it is difficult to distinguish associations from causal relationships. Nevertheless, it is apparent that the dysbiotic gut microbial community elicits inflammatory features extending beyond the enteric system and stimulates aberrant and pathological brain changes. Intestinal homeostasis relies on secreted IgA that coats pathogenic bacteria and blocks their contact with epithelial receptors to avert inflammatory responses. We will test the idea that IgA-coated bacteria (IgA-biome) in the dysbiotic intestine are pathogenic and responsible for the direct potentiation of AD. Our preliminary data using a transgenic AppNL-G-F mouse model of AD demonstrated a significant increase in the levels of IgA-coated fecal bacteria in female mice. Moreover, 16s rRNA sequencing of IgA sorted bacteria (IgA-seq) from 12-month-old female AppNL-G-F and C57BL/6 wild-type mice identified distinct differences in the microbial taxa coated by IgA. These data were concomitant with behavior changes seen only in the female AppNL-G-F mice suggesting a nexus between the IgA-biome, gut, and brain. We will fully characterize the longitudinal changes in the IgA-biome by IgA-seq in Aim one and determine whether distinct IgA coated bacteria correlate with changes in immune phenotype, memory, gliosis, and -amyloid accumulation. In Aim two, we will validate the role of IgA in the dysbiosed AD gut by oral gavage transfer of IgA-biome from old into young mice and assess sex and genotype-dependent changes in behavior, gliosis, - amyloid accumulation, and peripheral and intestinal immunomodulatory changes. Our work will provide a new understanding of the IgA-biome as a contributor to brain changes in AD and may be relevant to other neurodegenerative conditions. We will also identify the unique age and disease patterns of IgA-biome taxa that can be potential diagnostic biomarkers and therapeutic targets.