Jujuboside A promotes Aβ clearance and ameliorates cognitive deficiency in Alzheimer's disease through activating Axl/HSP90/PPARγ pathway

Rationale: It has been reported that peroxisome proliferator activated receptor. (PPAR gamma) level decreases significantly in the brains of Alzheimer's disease (AD) patients and mice models, while the mechanism is unclear. This study aims to unravel the mechanism that amyloid beta (A beta) decreases PPAR gamma and attempted to discover lead compound that preserves PPAR gamma. Methods: In APP/PS1 transgenic mice and A beta treated microglia, the interaction between HSP90 and PPAR gamma were analyzed by western blot. Using a PPRE (PPAR gamma responsive element) containing reporter cell line, compounds that activate PPAR gamma activity were identified. After genetic ablation or pharmacological inhibition of potential target pathways, the target of jujuboside A (JuA) was discovered through Axl/HSP90 beta. After oral administration or intrathecal injection, the anti-AD activity of JuA was evaluated by Morris water maze (MWM) test and object recognition test. Soluble A beta 42 levels and plaque numbers after JuA treatment were detected by thioflavin S staining, and the activation of microglia was assayed by immunofluorescence staining against Iba-1. Results: We found that A beta stress decreased heat shock protein 90 beta (HSP90 beta), subsequently reduced the abundance of PPAR gamma, and down-regulated A beta clearance-related genes in BV2 cells and primary microglia. We identified that JuA stimulated the expression of HSP90 beta, strengthened the interaction between HSP90 beta and PPAR gamma, preserved PPAR gamma levels, and thus effectively promoted the clearance of A beta 42. We demonstrated that JuA increased HSP90 beta expression through Axl/ERK pathway. JuA significantly ameliorated cognitive deficiency in APP/PS1 transgenic mice, meanwhile, JuA significantly reduced the soluble A beta 42 levels and plaque numbers in the brain. Notably, the therapeutic effects of JuA were dampened by R428, an Axl inhibitor. Conclusions: This study suggests that the up-regulation of HSP90 beta by JuA through Axl is a potential therapeutic strategy to facilitate A beta 42 clearance and ameliorate cognitive deficiency in AD.