摘要
阿尔茨海默病(Alzheimer’s disease,AD)是导致进行性痴呆的主要原因,其特征为记忆力丧失和渐进性神经认知功能障碍。然而,其分子机制尚未完全明了。为阐明导致AD的分子机制,我们设计了一个集成的分析工作流程,以确定在AD患者颞叶皮质RNA测序(RNA-seq)数据中的关键调控目标。分析发现可溶性转化生长因子β受体3(s TGFBR3)是AD中的一个关键靶点。sTGFBR3在AD患者和AD小鼠模型中异常升高。通过慢病毒载体表达shRNA的方式沉默sTGFBR3后,由淀粉样前体蛋白(APP)/PS1和链脲佐菌素(STZ)诱导的AD小鼠的空间学习能力下降和记忆缺陷可得到改善。其机制可能是sTGFBR3的缺乏增强了TGF-β信号并抑制了NF-κB途径,从而减少了疾病相关微胶质细胞(DAMs)的数量,抑制了促炎活性并增加了DAMs的吞噬活性。此外,sTGFBR3的缺乏可显著减轻由脂多糖(LPS)引起的急性神经炎症,并缓解STZ诱导的神经功能障碍。综上所述,sTGFBR3可能是AD治疗的一个有效的潜在靶标。
Alzheimer's disease(AD)is a major cause of progressive dementia characterized by memory loss and progressive neurocognitive dysfunction.However,the molecular mechanisms are not fully understood.To elucidate the molecular mechanism contributing to AD,an integrated analytical workflow was deployed to identify pivotal regulatory target within the RNA-sequencing(RNA-seq)data of the temporal cortex from AD patients.Soluble transforming growth factor beta receptor 3(sTGFBR3)was identified as a critical target in AD,which was abnormally elevated in AD patients and AD mouse models.We then demonstrated that sTGFBR3 deficiency restored spatial learning and memory deficits in amyloid precursor protein(APP)/PS1 and streptozotocin(STZ)-induced neuronal impairment mice after its expression Was disrupted by a lentiviral(LV)vector expressing shRNA,Mechanistically,sTGFBR3 deficiency augments TGF-β signaling and suppressing the NF-kB pathway,thereby reduced the number of disease-associated microglia(DAMs),inhibited proinflammatory activity and increased the phagocytic activity of DAMs.Moreover,sTGFBR3 deficiency significantly mitigated acute neuroinflammation provoked by lipopolysaccharide(LPS)and alleviated neuronal dysfunction induced by STZ.Collectively,these results position sTGFBR3 as a promising candidate for therapeutic intervention in AD.
出处
《神经损伤与功能重建》
2024年第12期F0003-F0003,共1页
Neural Injury and Functional Reconstruction
