Jujuboside A promotes Aβ clearance and ameliorates cognitive deficiency in Alzheimer's disease through activating Axl/HSP90/PPARγ pathway.
Jujuboside A promotes Aβ clearance and ameliorates cognitive deficiency in Alzheimer's disease through activating Axl/HSP90/PPARγ pathway.
复制标题
Jujuboside A 通过激活 Axl/HSP90/PPAR gamma 通路促进 Aβ 清除并改善阿尔茨海默病的认知缺陷
作者：
Zhang M;Qian C;Zheng ZG;Qian F;Wang Y;Thu PM;Zhang X;Zhou Y;Tu L;Liu Q;Li HJ;Yang H;Li P;Xu X
理由：据报道，过氧化物酶体增殖物激活受体γ (PPARγ)水平在阿尔茨海默病（AD）患者和小鼠模型的大脑中显著降低，但其机制尚不清楚。本研究旨在揭示淀粉样蛋白β (Aβ)降低PPARγ的机制，并试图发现保存PPARγ的先导化合物。方法：在APP/PS1转基因小鼠和Aβ处理的小胶质细胞中，采用western blot方法分析HSP90与PPARγ的相互作用。使用含有报告细胞系的PPRE （PPARγ响应元件），鉴定了激活PPARγ活性的化合物。在基因消融或药物抑制潜在靶标途径后，通过Axl/HSP90β发现了JuA的靶标。经口服或鞘内注射后，采用Morris水迷宫（MWM）试验和物体识别试验评价JuA抗ad活性。采用硫黄素S染色检测JuA处理后的可溶性Aβ42水平和斑块数量，免疫荧光法检测Iba-1对小胶质细胞的活化作用。结果：我们发现Aβ应激降低了BV2细胞和原代小胶质细胞中热休克蛋白90β (HSP90β)，从而降低了PPARγ的丰度，并下调了Aβ清除相关基因。我们发现JuA刺激了HSP90β的表达，增强了HSP90β与PPARγ的相互作用，保持了PPARγ的水平，从而有效地促进了Aβ42的清除。我们证明JuA通过Axl/ERK途径增加HSP90β的表达。JuA显著改善APP/PS1转基因小鼠的认知缺陷，同时显著降低脑内可溶性Aβ42水平和斑块数量。值得注意的是，Axl抑制剂R428抑制了JuA的治疗效果。结论：本研究提示JuA通过Axl上调HSP90β是促进a β42清除和改善AD认知缺陷的潜在治疗策略。
Rationale: It has been reported that peroxisome proliferator activated receptor γ (PPARγ) 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 β (Aβ) decreases PPARγ and attempted to discover lead compound that preserves PPARγ. Methods: In APP/PS1 transgenic mice and Aβ treated microglia, the interaction between HSP90 and PPARγ were analyzed by western blot. Using a PPRE (PPARγ responsive element) containing reporter cell line, compounds that activate PPARγ activity were identified. After genetic ablation or pharmacological inhibition of potential target pathways, the target of jujuboside A (JuA) was discovered through Axl/HSP90β. 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 Aβ42 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 Aβ stress decreased heat shock protein 90 β (HSP90β), subsequently reduced the abundance of PPARγ, and down-regulated Aβ clearance-related genes in BV2 cells and primary microglia. We identified that JuA stimulated the expression of HSP90β, strengthened the interaction between HSP90β and PPARγ, preserved PPARγ levels, and thus effectively promoted the clearance of Aβ42. We demonstrated that JuA increased HSP90β expression through Axl/ERK pathway. JuA significantly ameliorated cognitive deficiency in APP/PS1 transgenic mice, meanwhile, JuA significantly reduced the soluble Aβ42 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 HSP90β by JuA through Axl is a potential therapeutic strategy to facilitate Aβ42 clearance and ameliorate cognitive deficiency in AD.