Atractylenolide III Attenuated Neurotoxicity in Alzheimer's Disease via AMPK/GSK3β/Nrf2/HO-1 Signaling Pathway.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and widespread neuroinflammation. Atractylenolide III (AT-III), the primary active compound in Atractylodes macrocephala Koidz, has shown various health-promoting effects, including antioxidant properties and neuroprotection. However, the anti-AD molecular mechanism of AT-III remains to be further investigated. FAD4T mice were treated with AT-III for 4 weeks, and the neuroprotective effect of AT-III was subsequently evaluated by cognitive performance, histopathology, transcriptomic profiling, and 16S rRNA sequencing. SH-SY5Y cells were also used to verify the roles of AT-III on the AMPK/GSK3β/Nrf2/HO-1 pathway. AT-III significantly improved cognitive function, evidenced by a decreased escape latency and increased number of platform crossings in the Morris water maze (MWM) test and an increased alternation ratio in the Y-maze test. Histological analysis revealed that AT-III alleviated neuronal loss, reduced apoptosis and glial activation, and reduced Aβ deposition in the hippocampus. Biochemical assessments indicated that AT-III decreased oxidative stress and reduced neuroinflammation. Additionally, AT-III improved the diversity of the gut microbiota, including an increase in Ileibacterium and a decrease in Candidatus_Saccharimonas. Mechanistically, AT-III activated the AMPK/GSK3β/Nrf2/HO-1 signaling pathway both in vivo and in vitro. We further confirmed that AT-III significantly ameliorates Aβ1-42-induced cytotoxicity, excessive ROS production, and apoptosis in SH-SY5Y cells. However, the protective effects of AT-III were partially abolished by Compound C (an AMPK inhibitor). Our study demonstrates that AT-III mitigated neurodegenerative damage in AD by suppressing microglial activation and neuroinflammation through the AMPK/GSK3β/Nrf2/HO-1 signaling, which suggests that AT-III might be a novel therapeutic strategy for the inhibition of AD.