Butyrate antagonizes Annexin A2-mediated tauopathy via Annexin A1 reciprocity in Alzheimer's disease.

Abstract

BACKGROUND: The balance between Annexin A1 (AnxA1), a pro-resolving mediator, and Annexin A2 (AnxA2), a pro-inflammatory counterpart, is essential for immune homeostasis but remains poorly explored in Alzheimer's disease (AD). AIM: To evaluate butyrate's ability to restore AnxA1/AnxA2 equilibrium and attenuate tauopathy and neuroinflammation in cellular and aluminum chloride (AlCl)/d-galactose AD models. METHODS: In vitro, BV2 cells were used to study AnxA1/AnxA2 reciprocity in microglia, while retinoic acid-differentiated C6 cells with a neuron-like phenotype were employed to assess tau phosphorylation and AnxA1/AnxA2 interplay. In vivo, AlCl/d-galactose rats underwent behavioral testing, Western blotting, ELISA, and immunohistochemistry evaluating butyrate's effects on annexin balance, tau pathology, redox homeostasis, and acetylcholinesterase activity. RESULTS: In vitro, Aβ-suppressed AnxA1 and elevated AnxA2 in BV2 microglia, increasing TNF-α, and promoted GSK-3α/β-driven tau phosphorylation in differentiated C6 neuron-like cells through AnxA1/AnxA2 reciprocal regulation. Butyrate restored AnxA1, suppressed AnxA2/GSK-3β/TNF-α, and attenuated tau pathology. In vivo, prophylactic butyrate preserved hippocampal cytoarchitecture, improved cognition, reduced amyloid burden, normalized redox balance, inhibited acetylcholinesterase, and re-equilibrated hippocampal/systemic AnxA1/AnxA2 with decreased p-tau. CONCLUSION: Butyrate modulates the AnxA1/AnxA2 axis to suppress neuroinflammation and tauopathy, positioning it as a gut-brain axis therapeutic for sporadic AD.