背景:阿尔茨海默病是一种神经系统疾病,其特征是淀粉样β肽(Aβ)和脂多糖(LPS)的积累,导致突触功能障碍,细胞死亡,还有神经炎症.适应不良的未折叠蛋白反应(UPR),过度自噬,和焦亡加重疾病。褪黑激素(MEL)和羟基丁酸酯(BHB)在降低Aβ病理学方面均显示出希望。这项研究的目的是了解BHB和MEL如何影响UPR,自噬,和Aβ1-42和LPS诱导的SH-SY5Y细胞的焦亡途径。
方法:用BHB处理人神经母细胞瘤SH-SY5Y细胞,MEL,或暴露于Aβ1-42和LPS后两者的组合。使用MTT测试确定细胞活力,和基因表达水平的UPR(ATF6,PERK,和CHOP),自噬(Beclin-1,LC3II,P62和Atg5),和焦亡相关标志物(NLRP3,TXNIP,IL-1β,和NFκB1)使用定量实时PCR(qRT-PCR)测定。为了进行统计分析,采用了单向方差分析,其次是Tukey的事后测试。
结果:在Aβ1-42和LPS存在下,BHB和MEL显着增加SH-SY5Y细胞的活力。两种化合物都抑制了适应不良的UPR和自噬相关基因的表达,以及Aβ1-42和LPS诱导的SH-SY5Y细胞引起的炎症和促性腺激素标志物。
结论:BHB和MEL通过减少适应不良的UPR拯救Aβ1-42和LPS诱导的SH-SY5Y细胞中的神经元,过度自噬,和焦亡。需要更多的研究来充分理解其有益作用背后的过程,并发现其在神经退行性疾病治疗中的实际应用。
BACKGROUND: Alzheimer\'s disease is a neurological disease characterized by the build-up of amyloid beta peptide (Aβ) and lipopolysaccharide (LPS), which causes synapse dysfunction, cell death, and neuro-inflammation. A maladaptive unfolded protein response (UPR), excessive autophagy, and pyroptosis aggravate the disease. Melatonin (MEL) and hydroxybutyrate (BHB) have both shown promise in terms of decreasing Aβ pathology. The goal of this study was to see how BHB and MEL affected the UPR, autophagy, and pyroptosis pathways in Aβ1-42 and LPS-induced SH-SY5Y cells.
METHODS: Human neuroblastoma SH-SY5Y cells were treated with BHB, MEL, or a combination of the two after being exposed to A β1-42 and LPS. Cell viability was determined using the MTT test, and gene expression levels of UPR (ATF6, PERK, and CHOP), autophagy (Beclin-1, LC3II, P62, and Atg5), and pyroptosis-related markers (NLRP3, TXNIP, IL-1β, and NFκB1) were determined using quantitative Real-Time PCR (qRT-PCR). For statistical analysis, one-way ANOVA was employed, followed by Tukey\'s post hoc test.
RESULTS: BHB and MEL significantly increased SH-SY5Y cell viability in the presence of A β1-42 and LPS. Both compounds inhibited the expression of maladaptive UPR and autophagy-related genes, as well as inflammatory and pyroptotic markers caused by Aβ1-42 and LPS-induced SH-SY5Y cells.
CONCLUSIONS: BHB and MEL rescue neurons in A β1-42 and LPS-induced SH-SY5Y cells by reducing maladaptive UPR, excessive autophagy, and pyroptosis. More research is needed to fully comprehend the processes behind their beneficial effects and to discover their practical applications in the treatment of neurodegenerative disorders.