Transthyretin Contributes to Hippocampal Blood-Brain Barrier Recovery Following Intestinal Inflammation, with Reduced Expression in Alzheimer’s Disease

Abstract

Background The blood-brain barrier (BBB) is increasingly recognized as an active immunoregulatory interface that responds dynamically to systemic inflammation. As intestinal inflammation can influence brain homeostasis through the gut-brain axis, the endogenous mechanisms that preserve BBB integrity during gut-derived inflammatory stress remain poorly understood. Methods and Results We combined dextran sulfate sodium-induced colitis, fecal microbiota transplantation, aged mice, APP/PS1 mice, human Alzheimer’s disease (AD) brain tissue, single-cell RNA sequencing, in vivo BBB permeability assays, and gain- and loss-of- function approaches to investigate adaptive neurovascular responses to gut inflammation and their mechanism in maintaining BBB integrity. Intestinal inflammation induced a region- specific adaptive response characterized by increased hippocampal vascular remodeling and partial restoration of BBB integrity following the initial inflammatory insult. Single-cell transcriptomic analysis identified a transthyretin (TTR)-enriched vascular-associated microglial state accompanying these neurovascular changes. Functional studies demonstrated that TTR contributes to maintaining BBB integrity by promoting endothelial homeostasis and limiting endothelial endocytosis, consistent with modulation of FcRn-associated transport pathways. This adaptive neurovascular response was progressively attenuated in aged mice and APP/PS1 mice and was accompanied by reduced vascular TTR expression in human AD brains. Conclusion These findings identify TTR as a contributor of adaptive neurovascular homeostasis during gut-derived neuroinflammation. Impairment of this homeostatic response with aging and AD may contribute to persistent BBB dysfunction and chronic neuroinflammation, highlighting neurovascular resilience as a potential therapeutic target.