Combined supplementation of short-chain fatty acids reduces hyperphosphorylation of Tau at T181,T231 and S396 sites and improves cognitive impairment in a chemically induced AD mouse model via regulation of HDAC and Keap1

Abstract

Alzheimer's disease (AD) is characterized by the pathological hallmarks of β-amyloid deposition and Tau protein hyperphosphorylation, with memory loss and cognitive dysfunction as its primary clinical manifestations. The incidence of AD has been progressively increasing in recent years. Short-chain fatty acids (SCFAs), key effector molecules in host-gut microbial interactions, play a crucial role in maintaining central nervous system homeostasis. In this study, AD mouse model was established via AlCl₃/D-gal induction. The effects of mixed SCFA intervention on spatial learning and memory in AD model mice were assessed using behavioral tests, including the Morris Water Maze. Levels of pro-inflammatory cytokines and activities of oxidative stress-related enzymes in brain and colon tissues were quantified using ELISA and commercial kits. Key protein expression levels were analyzed by Western blot, immunohistochemistry, and immunofluorescence. Results demonstrated that SCFAs significantly alleviated cognitive dysfunction in AD model, reduced Tau hyperphosphorylation at T181, T231 and S396 sites, suppressed pro-inflammatory cytokine release, and enhanced antioxidant capacity, but with no reversal in elevated Aβ levels in AD model. Mechanistically, SCFAs inhibited glial cell activation, upregulated MCT-1 and tight junction proteins in the blood-brain barrier and strengthened gut-brain barrier integrity, potentially regulating small molecule trans-barrier transport. Furthermore, examination of relevant protein expressions revealed that SCFAs activated HDAC1 and inhibited overexpressed HDAC3 and Keap-1 in AD mice model. These findings suggest that SCFAs may regulate epigenetic modifications in the brain of AD to exert neuroprotective effects. This study provides novel evidence supporting the potential of symbiotic microbe-derived SCFAs in alleviating AD.

Keywords: Alzheimer's disease (AD); HDAC; SCFAs; Tau phosphorylation; physiological barrier.