Mechanisms underlying edible exosome-like nanoparticles for prevention of brain inflammation

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Brain chronic inflammation is a hallmark of the aging process, and promotes the progression of many brain diseases. Compelling evidence shows that healthy edible plants have important physiological roles for normal brain function and can prevent neuroinflammatory processes. However, mechanistic studies in the brain have primarily focused on single or individual factors from edible plants, which most likely do not represent the results generated from multiple factors that are provided in a healthy diet consumed daily. Recently, a tiny nanoparticle called an exosome-like nanoparticle (ELN) has been isolated from a number of edible plants. ELNs consists of lipids, proteins, and RNAs. We have demonstrated that ELNs, like prebiotics, are taken up by intestinal bacteria, resulting in inhibition of mouse colitis. However, whether these edible plant- derived nanoparticles have a direct effect on the brain is not clear. In this study, we will provide cellular and molecular insight into how ELNs modulate neuroimmune function via a gut-brain axis by targeting microglial cells that benefits the brain. Indispensable to this proposal is the use of a mouse aging model to investigate mechanistic details that will facilitate developing ELNs as a potential new class of prebiotic to target specific components involved in brain inflammation. Based on these findings it is tempting to speculate that the clinical profile of at least some brain anti-inflammation therapeutics can be improved by interventions relying on one or more edible plant-derived ELNs. This finding urgently awaits experimental confirmation, which is what we proposed to investigate in this proposal. From a clinical application standpoint and as proof-of-concept, in this study, our hypothesis is that multiple factors carried by garlic ELNs (GaELN) target to microglial cells simultaneously to inhibit brain inflammation in aged mice. This will be tested in a mouse aging model that mimics human aging process. The plan to test our hypothesis is outlined in three specific aims. Our proposed studies will determine: (1) Determine and evaluate if garlic ELN (GaELN) phosphatidic acid (PA) stimulated BASP1 domain(s) that binds to calmodulin (CaM) prevents c-MYC mediated brain inflammation in aged mice; (2) Evaluate whether GaELN nc-sRNA21 contributes to inhibition of brain inflammation by enhancing the transporting of c-MYC-nick into exosomes in a Rab11a dependent manner; and (3) Evaluate whether GaELN induces a switch to secretion of CYLD+exosomes with immune tolerant cargos. Upon accomplishing this proposed study, the study will lead to identification of new therapeutic targets and potential ELN based interventions for treating brain inflammation. In addition, findings will provide a foundation to further study whether oral administration of customized ELNs isolated from different plants will have a synergistic/additive effect on prevention or treatment of chronic inflammatory brain related diseases. Therefore, this study is a highly translational study aimed at finding new therapeutic targets for brain inflammation.