Abstract:
The brain is not an immune-privileged organ but rather an immune-specialized one. The bidirectional communication between the brain and peripheral organs, including the gut, is key for brain health as brain-resident microglia send and receive signals from the peripheral blood and organs. This neuroimmune crosstalk deteriorates with ageing, environmental exposures, stress, lifestyle choices, etc. and contributes to age-related neurodegenerative diseases (NDs) which are multi-system, heterogeneous, and complex diseases involving peripheral organs and the brain. Gene-by-environment interactions combine with aging to create the perfect storm for development of NDs and the immune system plays a key role as the arbiter of this interplay. Clinical data and pre-clinical models of NDs reveal that innate and adaptive immune dysfunction in both central and peripheral immune compartments. Specifically, our group found that immunological stimulation of mouse or human peripheral blood mononuclear cells ex vivo enables detection of dysfunctional immune/inflammatory traits in aging individuals and in those carrying disease-relevant mutations, a strategy with implications for stratification of patients for clinical trials. Metabolic dysregulation and chronic inflammatory systemic disease have also been implicated in risk for NDs, raising the interesting possibility that targeting these conditions outside the brain in mid-life may protect the brain decades later. Leveraging multi-disciplinary approaches including multi-color flow cytometry, single-cell and spatial transcriptomics and proteomics, and machine learning, our group has generated data implicating gut dysbiosis, iron dysregulation, and short-chain fatty acid depletion as mechanisms that may increase risk for age-related ND in inflammatory bowel disease (IBD) and Crohn’s. Our findings lend support to the body-brain hypothesis of ND and suggest that translational neuroimmunological approaches will enable timely and precise use of immunomodulatory interventions to delay, slow, and/or prevent ND.