Armillariella tabescens polysaccharide targets microglial glycolysis to alleviate sleep deprivation-induced neuroinflammation through the mTOR signaling pathway.

Authors

Yuchen Zhang, ShuYu Yang, Siting Ran, Minru Du, Jiaqi Chen, Mengdan Cen, Yi Gu, Jiahui Liao, Yunle Liu, Ruifen Zhang, Jie Wang

Published in

Phytomedicine : international journal of phytotherapy and phytopharmacology. Volume 160. Pages 158687. Aug 04, 2026. Epub Aug 04, 2026.

Abstract

Neurodegenerative diseases (NDs) impose a growing global burden on aging populations, characterized by progressive neuronal loss, synaptic dysfunction, and limited therapeutic options. Natural polysaccharides have attracted considerable attention as potential neuroprotective agents due to their diverse bioactivities and favorable safety profiles.
This study aimed to isolate and characterize a homogeneous polysaccharide from the medicinal fungus Armillariella tabescens (ATEP), systematically evaluate its anti-neuroinflammatory and neuroprotective effects against NDs, and elucidate the underlying molecular mechanisms.
A combined approach of network pharmacology prediction and experimental validation was employed, using both in vivo (sleep-deprived ND mouse model) and in vitro (LPS-stimulated BV2 microglial cells) models to assess the neuroprotective effects and mechanism of ATEP.
ATEP was isolated and purified, and its structural characteristics were determined. Network pharmacology was performed to predict core targets and pathways. In a sleep-deprived ND mouse model, cognitive function, endogenous antioxidant capacity, neuroinflammation, neurotoxic protein levels, and neuronal apoptosis were assessed. In vitro, BV2 microglial cells were used to evaluate microglial polarization, glycolytic metabolism, and mitochondrial function following ATEP treatment.
ATEP (99.3% purity) exhibited an average molecular weight of 39.17 kDa and an α‑configured pyranose backbone. Network pharmacology identified IL-6, TNF-α, IL-1β, and mTOR as core targets. In vivo, ATEP significantly improved cognitive function, enhanced antioxidant capacity (elevated SOD, CAT, and GSH), suppressed neuroinflammation (reduced IL-6, IL-1β, and TNF-α), downregulated neurotoxic proteins (APP, BACE1, p-Tau), and inhibited neuronal apoptosis in the hippocampus. In vitro, ATEP dose-dependently inhibited LPS-induced M1 polarization and promoted M2 polarization, corrected the aerobic glycolytic shift (reduced lactate, increased ATP, downregulated Pfkfb3 (a key glycolytic enzyme) and GLS (a glutaminolysis key enzyme), and improved mitochondrial function.
ATEP exerts neuroprotective effects by inhibiting mTOR signaling pathway activation, which drives mTOR-dependent glycolytic metabolic reprogramming and subsequent microglial M1-to-M2 polarization, thereby enhancing antioxidant defenses, mitigating neuroinflammation, and preserving synaptic integrity. These findings highlight ATEP as a structurally defined natural candidate for the development of metabolism-targeting neuroprotective agents against NDs.

PMID:
42603527
Bibliographic data and abstract were imported from PubMed on 16 Aug 2026.

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