Natural Microbial Experience Increases Infiltration of T Cells in the Brains of Alzheimer’s Disease Mice 2258422

Abstract Introduction The immune environment of the brain plays a major role in neurodegenerative conditions such as Alzheimer’s disease. The abnormally clean facilities in which laboratory mice are kept limit immune experience and cause major concerns regarding the translatability of research to humans. These facilities, although not germ-free, lack the normal exposures to diverse commensal and environmental microorganisms experienced by mice in the wild or diverse environments such as a pet store. By breeding inbred lab mice that have previously experienced exposure to the dirty bedding of pet store mice, we can generate “bred dirty” mice with immune systems that mirror those of adult humans more closely. It is unclear whether these immune changes extend to the brain and whether this plays a role in neurodegenerative disease. Methods We used the P301s transgenic mouse model of Alzheimer’s disease that accumulates age-dependent tau pathology. We exposed these mice to dirty bedding obtained from pet store mice, and bred them to establish a line of “bred dirty” tau-P301S mice and appropriate controls. At endpoint, we collected brain and spleen for flow cytometry, immunofluorescence, and bulk RNAseq. Results The proportions of CD3+ T cells, monocytes, and macrophages were significantly increased in the brains of the dirty tau-P301S mice compared to their clean tau-P301S counterparts. The brains of the dirty tau-P301S mice also showed an increase in the proportion of CD8+ T cells, specifically effector differentiated (CD62L-CD44+) CD8+ T cells. The proportion of activated (CD11c+) microglia was increased in tau-P301S mice but unaffected by dirty status. Conclusion Disease-associated infiltration of adaptive immune cells into the brain is amplified by dirty status without grossly affecting microglial activation. Given the increasingly recognized role of T cells in Alzheimer’s disease pathogenesis, our results suggest that more immune educated models might better represent the role of T cells in neurodegenerative disease. Funding Source Mayo Clinic and The Translational Genomics Research Institute Topic Categories Neuroimmunology (NEUR)