Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A2/prostaglandin E2 content

Abstract

Taxifolin is a potent flavonoid with anti-inflammatory activity. Taxifolin has been reported to decrease the accumulation of β-amyloid (Aβ), and reduce Aβ-induced neurotoxicity. However, the detail molecular mechanism of taxifolin against Aβ-induced neurotoxicity is largely unknown. In this study, we revealed the protective effects and the underlying mechanisms of taxifolin on the impairments of cognitive function and synapse formation induced by soluble Aβ oligomers. Our results showed that taxifolin prevented neuronal cell death in a concentration-dependent manner. The recognition memory in novel object recognition tasks and the spatial memory in Morris water maze tests are significantly lower in the Alzheimer’s disease (AD) model mice induced by hippocampal injection of Aβ42. Taxifolin treatment prevented the recognitive and spatial memory deficits of the AD mice. 10 mg/kg taxifolin treatment also significantly prevented the decreased expression levels of PSD 95 induced by Aβ42. Live cell imaging study showed that 2 h pre-treatment of taxifolin prevented the decrease in the number of filopodium and spine induced by Aβ42 oligomers. Aβ42 oligomers significantly increased the production of cytosolic phospholipase A2 (cPLA2), a crucial enzyme of pro-inflammatory mediator, and prostaglandin E2 (PGE2), a neuroinflammatory molecule. Taxifolin significantly reduced the content of cPLA2 and PGE2 induced by Aβ42 both in the primary hippocampal neurons and hippocampal tissues. These results indicated that taxifolin might prevent Aβ42 oligomer-induced synapse and cognitive impairments through decreasing cPLA2 and PGE2. Our study provided novel insights into the cellular mechanisms for the protective effects of taxifolin on AD.

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Fig. 1: Taxifolin prevented oligomeric-Aβ42-induced SH-SY5Y cell death in a dose-dependent manner.
Fig. 2
Fig. 3: Effects of taxifolin on oligomeric-Aβ42-induced spatial learning and memory deficits in a water maze test in mice.
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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-β protein

PGE2 :

Prostaglandin E2

SO Aβ:

Soluble oligomers of Aβ

cPLA2 :

Cytosolic phospholipase A2

AA:

Arachidonic Acid

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Acknowledgments

This work was supported by grants from The National Natural Science Foundation of China (81771166 and 81471398), Natural Science Foundation of Zhejiang Province (LY16H090001 and LY14H090004), Natural Science Foundation of Ningbo (2015A610211), Ningbo municipal innovation team of life science and health (2015C110026), and the K.C.Wong Magna Fund in Ningbo University.

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Correspondence to Shujun Xu.

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Wang, Y., Wang, Q., Bao, X. et al. Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A2/prostaglandin E2 content. Metab Brain Dis 33, 1069–1079 (2018). https://doi.org/10.1007/s11011-018-0207-5

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Keywords

  • Taxifolin
  • Alzheimer’s disease
  • Cognitive impairments
  • Synapse
  • Prostaglandin E2
  • Cytosolic phospholipase A2