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

We previously found diosgenin, an herbal drug-derived steroid sapogenin, to be remarkably effective at restoring A ss-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 A ss-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, alpha-tubulin was detected by immunoprecipitation. After A ss treatment, alpha-tubulin expression was greatly reduced in the degenerated axons, suggesting that a decline in alpha-tubulin may be one of the factors which correlates with axonal disruption in AD pathology. We hypothesized that the degradation of alpha-tubulin is triggered by the chaperone activity of HSC70. However, diosgenin significantly normalized the alpha-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.