20(S)-protopanaxadiol targets brain-enriched adenylate kinase 5 to improve cognitive function via regulating hippocampal neural plasticity.

Abstract

BACKGROUND: Ginseng is used as a nutritional supplement for cognitive impairment, but its mechanism of action is not yet fully understood. Previously, we have discovered that adenylate kinase 5 (AK5) is the target of the ginsenoside metabolite 20(S)-protopanaxadiol (PPD), and PPD could increase the activity of AK5. PURPOSE: The aim of this study is to explore the possible mechanism by which PPD improves cognitive impairment based on AK5 and its associated neural plasticity. METHODS: After knocking down AK5 with AAV-shRNA-AK5 or establishing the d-galactose-induced mouse model of cognitive impairment, we applied behavioral tests to estimate the learning and memory ability of mice. The activity, mRNA and protein expression of AK5 was then detected by enzyme activity assay, qPCR and western blot, respectively. The alterations in hippocampal synaptic plasticity and neurogenesis were observed using qPCR, western blot, Nissl staining and immunofluorescence staining. RESULTS: Firstly, we observed that knocking down AK5 in hippocampal neurons of mice caused cognitive impairment behaviors and reduced hippocampal neural plasticity. Moreover, this effect was basically consistent with that observed in d-galactose-induced mice. Subsequently, behavioral experiments showed that PPD might assist d-galactose-induced mice with their learning and memory difficulties. A series of results showed that PPD could partially restore the decrease in AK5 expression and enzymatic activity, as well as the impaired neural plasticity in the hippocampus of d-galactose-induced mice. Finally, it is worth noting that the improvement effect of PPD on the cognitive impairment of d-galactose-induced mice was almost completely eliminated after the knockdown of AK5 in hippocampal neurons. CONCLUSION: Overall, the results of our investigation showed the crucial role of AK5 in mediating neural plasticity and revealed AK5 as a therapeutic target for PPD to alleviate cognitive impairment.