Abstract 1620 Kinases in Gut-Liver-brain communication and neuroinflammation

Background and Aims: Alzheimer's disease (AD) is the commonest form of dementia where its incidence is rising and expected to quadruple worldwide by 2050. Type-2 diabetes (T2D) is a risk factor for AD, where AD is now being considered as Type-3 diabetes (T3D). Though we all say, "you are what you eat, and everyone has a gut-feeling", the role of gut in AD pathology is still not completely clear. Previously we reported reduced expression of intestinal Janus kinase-3 (Jak3), a non-receptor tyrosine kinase in humans with type-2 diabetes (T2D). In this study we model total body and tissue-specific Jak3-deficiency in mice and demonstrate its role in T2D and AD through interorgan communication mediated by gut-liver-brain axis. Our data show that high fat diet (HFD) suppresses Jak3 expression both in intestinal mucosa and in brain of wild-type mice and genetic manipulation-led Jak3-deficiency causes gut-dysbiosis, T2D, and AD-like symptoms. Methodology: Global (Jak3-KO) and intestinal epithelial cell-specific conditional (IEC-Jak3-KO) mice were used to measure fasting blood glucose, glucose tolerance, serum insulin, cognitive functions, western analysis, flow-cytometry, immunofluorescence microscopy, and 16s rRNA sequencing of fecal pellets. Results: We reveal that Jak3 deficiency leads to gut-dysbiosis, intestinal and liver inflammation and these together compromises TREM-2 functions-mediated activation of microglial cells. Moreover, these increase TLR-4 expression and HIF1-a-mediated neuroinflammation in the brain. Altogether, these led to compromised microglial functions-mediated increased level of b-amyloid (Aβ) and hyperphosphorylated Tau (pTau) and cognitive impairments. Collectively, these data illustrate how the drivers of T2D promote cognitive impairment and demonstrate the underlying mechanism where diet-mediated impact on intestinal-Jak3 gut-liver-brain miscommunication, reduced microglial-TREM2 expression, microglial-activation, and compromised clearance of Aβ and pTau as the mechanism during T2D linked neuroinflammation and cognitive impairments. Conclusion: Thus, we not only demonstrate the tissue-specific role of Jak3 but also show the evidence of Gut-Liver-brain communication and cognitive impairments during Jak3 deficiency through mucosal tolerance, gut-dysbiosis, hepatitis, and neuroinflammation. Global Institute of Hispanic Health (GIHH), Discovery Foundation, Texas A&M University.