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Pseudoginsenoside-F11 attenuates cognitive dysfunction and tau phosphorylation in sporadic Alzheimer’s disease rat model

Abstract

We previously reported that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, significantly ameliorated Alzheimer’s disease (AD)-associated cognitive defects in APP/PS1 and SAMP8 mice by inhibiting Aβ aggregation and tau hyperphosphorylation, suggesting a potential therapeutic effect of PF11 in the treatment of AD. In the present study we further evaluated the therapeutic effects of PF11 on relieving cognitive impairment in a rat model of sporadic AD (SAD). SAD was induced in rats by bilateral icv infusion of streptozotocin (STZ, 3 mg/kg). The rats were treated with PF11 (2, 4, 8 mg·kg−1·d−1, ig) or a positive control drug donepezil (5 mg·kg−1·d−1, ig) for 4 weeks. Their cognitive function was assessed in the nest building, Y-maze, and Morris water maze tests. We showed that STZ icv infusion significantly affected the cognitive function, tau phosphorylation, and insulin signaling pathway in the hippocampus. Furthermore, STZ icv infusion resulted in significant upregulation of the calpain I/cyclin-dependent protein kinase 5 (CDK5) signaling pathway in the hippocampus. Oral administration of PF11 dose-dependently ameliorated STZ-induced learning and memory defects. In addition, PF11 treatment markedly reduced the neuronal loss, protected the synapse structure, and modulated STZ-induced expression of tau phosphorylation by regulating the insulin signaling pathway and calpain I/CDK5 signaling pathway in the hippocampus. Donepezil treatment exerted similar beneficial effects in STZ-infused rats as the high dose of PF11 did. This study highlights the excellent therapeutic potential of PF11 in managing AD.

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Fig. 1: Experimental design.
Fig. 2: PF11 ameliorated STZ-induced cognitive decline.
Fig. 3: PF11 alleviated STZ-induced neuronal death and synaptic damage.
Fig. 4: PF11 inhibited STZ-induced tau hyperphosphorylation in the hippocampus.
Fig. 5: PF11 attenuated STZ-induced tau hyperphosphorylation by reversing dysregulation of the IRS-1/PI3K/AKT/GSK-3β and calpain I/CDK5 signaling pathways.

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Designed research: LZ, XJH, JYY. Performed research: XJH, LZ, TSZ, XQL. Analyzed data: XJH, LZ. Wrote the manuscript: LZ. Revised the manuscript: XHC, JYY, CFW. All authors contributed substantially to this work and approved the final manuscript.

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Correspondence to Chun-fu Wu or Jing-yu Yang.

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Zhu, L., Hou, Xj., Che, Xh. et al. Pseudoginsenoside-F11 attenuates cognitive dysfunction and tau phosphorylation in sporadic Alzheimer’s disease rat model. Acta Pharmacol Sin 42, 1401–1408 (2021). https://doi.org/10.1038/s41401-020-00562-8

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Keywords

  • Alzheimer’s disease
  • pseudoginsenoside-F11
  • Tau hyperphosphorylation
  • insulin signaling pathway
  • calpain I/CDK5 signaling pathway
  • donepezil

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