Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2026
Butyrate antagonizes Annexin A2-mediated tauopathy via Annexin A1 reciprocity in Alzheimer's disease.
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Jayaswamy Pavan K, Ambrish Trupthi, Sangamesh Vinay C, Kellarai Adithi, Patil Prakash, Alexander Lobo Manuel, Shetty Praveenkumar
Аннотация
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 (AlCl3)/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, AlCl3/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, Aβ1-42 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.
AIM: To evaluate butyrate's ability to restore AnxA1/AnxA2 equilibrium and attenuate tauopathy and neuroinflammation in cellular and aluminum chloride (AlCl3)/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, AlCl3/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, Aβ1-42 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.