Diosgenin restores A\u03b2-induced axonal degeneration by reducing the expression of heat shock cognate 70 (HSC70)

Ximeng Yang,Chihiro Tohda

doi:10.1038/s41598-018-30102-8

Abstract

We previously found diosgenin, an herbal drug-derived steroid sapogenin, to be remarkably effective at restoring Aβ-induced axonal degeneration and improving memory function in model of Alzheimer’s disease (AD), 5XFAD mouse. In this study, we investigated the downstream signaling of diosgenin and explored new therapeutic targets in AD. We showed that the expression of heat shock cognate (HSC) 70 was increased in Aβ-treated neurons and in 5XFAD mice but was decreased by diosgenin treatment. In addition, knockdown of HSC70 significantly promoted axonal growth in neurons. As an association molecule of HSC70 in neurons, α-tubulin was detected by immunoprecipitation. After Aβ treatment, α-tubulin expression was greatly reduced in the degenerated axons, suggesting that a decline in α-tubulin may be one of the factors which correlates with axonal disruption in AD pathology. We hypothesized that the degradation of α-tubulin is triggered by the chaperone activity of HSC70. However, diosgenin significantly normalized the α-tubulin level, a potentially critical process for axonal formation. Our study indicated that reducing the HSC70 level is a new possible therapeutic target of axonal regeneration in AD.

Highlights

We previously found diosgenin, an herbal drug-derived steroid sapogenin, to be remarkably effective at restoring amyloid β (Aβ)-induced axonal degeneration and improving memory function in model of Alzheimer’s disease (AD), 5XFAD mouse
Heat shock cognate 70 (HSC70; protein sequence coverage: 39%, score: 309) was identified as a protein whose expression was increased in the 5XFAD mouse, but remarkably decreased by diosgenin administration (Fig. 1C,D, respectively)
HSC70 was identified as a protein whose expression was increased in the 5XFAD mouse and drastically decreased by diosgenin administration

Summary

Introduction

An herbal drug-derived steroid sapogenin, to be remarkably effective at restoring Aβ-induced axonal degeneration and improving memory function in model of Alzheimer’s disease (AD), 5XFAD mouse. We previously found that diosgenin, an herbal drug-derived steroid sapogenin, restored Aβ-induced axonal atrophy in neurons and improved memory function in a mouse model of AD, 5XFAD mice[2]. The 5XFAD (Tg6799) mouse co-expresses mutant human amyloid precursor protein (APP; the Swedish mutations: K670N and M671L; the Florida mutation: I716V; the London mutation: V717I) and presenilin-1 (PS1; M146L and L286V) genes in neurons[3] These five familial AD mutations act together to increase the level of Aβ1–42 peptide in the brain. The goal of this study was to provide scientific support for the use of diosgenin as a curative drug for AD and to suggest new possible therapeutic targets in AD by exploring diosgenin signaling

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Conclusion