Cornel iridoid glycoside induces autophagy to protect against tau oligomer neurotoxicity induced by the activation of glycogen synthase kinase-3β

Abstract

Tau oligomers are the etiologic molecules of Alzheimer’s disease, and correlate strongly with neuronal loss and exhibit neurotoxicity. Recent evidence indicates that small tau oligomers are the most relevant toxic aggregate species. The aim of the present study was to investigate the mechanisms of cornel iridoid glycoside (CIG) on tau oligomers and cognitive functions. We injected wortmannin and GF-109203X (WM/GFX, 200 μM each) into the lateral ventricles to induce tau oligomer and memory impairment in rats. When orally administered with CIG at 60 and 120 mg/kg/day for 14 days, CIG decreased the escape latency in the Morris water maze test. We also found that CIG restored the expression of presynaptic p-synapsin, synaptophysin, and postsynaptic density-95 (PSD-95) decreased by WM/GFX in rat cortex. CIG reduced the accumulation of tau oligomers in the brain of WM/GFX rats and in cells transfected with wild type glycogen synthase kinase-3β (wtGSK-3β). In addition, CIG up-regulated the levels of ATG7, ATG12, Beclin-1, and LC3II in vivo and in vitro, suggesting the restoration of autophagy function. These results suggest that CIG could ameliorate memory deficits and regulate memory-associated synaptic proteins through the clearance of tau oligomers accumulation. Moreover, CIG clears tau oligomers by restoring autophagy function.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (Nos. 81703729, 81473373), National Science and Technology Major Project of China (No. 2015ZX09101-016), Beijing New Medical Discipline Grant (XK100270569), and Beijing High-level Health and Technical Personal Plan (Nos. 2011-1-7, 2014-2-014).

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Correspondence to Lin Li or Lan Zhang.

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Yang, C., Li, X., Zhang, L. et al. Cornel iridoid glycoside induces autophagy to protect against tau oligomer neurotoxicity induced by the activation of glycogen synthase kinase-3β. J Nat Med 73, 717–726 (2019). https://doi.org/10.1007/s11418-019-01318-3

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Keywords

  • Cornel iridoid glycoside
  • Autophagy
  • Tau oligomer
  • Glycogen synthase kinase-3β