家族性阿尔茨海默病(FAD)是一种复杂的多因素神经退行性疾病,目前尚无治愈性疗法。的确,到目前为止,还没有一种药物或干预措施被证明是完全有效的。因此,多靶点药物的联合治疗作为一种潜在的FAD治疗方法很有吸引力.这里,我们研究了联合曲米膦(TM)的潜力,姜黄素(CU),和JNK抑制剂SP600125(SP)作为FAD的治疗。该研究分析了这两种天然药物和这种药理抑制剂对细胞内淀粉样βiAβ积累的单独和联合作用;Ser202/Thr205上的高磷酸化蛋白TAU;线粒体膜电位(ΔkW);活性氧(ROS)的产生;氧化蛋白DJ-1;在Ser63/Ser73,TP53和带有16ACeninin的Icase-1的短暂性神经元(CC3)我们发现单剂量的TM(50μM),CU(10μM),或SP(1μM)有效地减少了一些,但不是全部,PSEN1I416TChLN中的病理标记物,而TM的组合,CU,和SP在高(50,10,1μM)浓度下有效地减少了IAβ,p-TAUSer202/Thr205、DJ-1Cys106-SO3和CC3标记-50%,-75%,-86%,和-100%,分别,在PSEN1I417TChLN中。尽管中(10,2,0.2)和低(5,1,0.1)浓度的组合显着降低了p-TAUSer202/Thr205,DJ-1Cys106-SO3和CC3的-69%和-38%,-100%和-62%,-100%和-62%,分别,与未处理的突变ChLN相比,这些组合没有改变IAβ。此外,H浓度的试剂组合能够恢复PSEN1I416T中ACh诱导的功能失调的Ca2内流反应。我们的数据表明,多靶点药物与抗淀粉样蛋白(TM,CU),抗氧化剂(例如,CU),和抗凋亡(TM,CU,SP)作用可能有利于减少FAD中iAβ诱导的ChLN损伤。
Familial Alzheimer\'s disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining
tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAβ; hyperphosphorylated protein TAU at Ser202/Thr205; mitochondrial membrane potential (ΔΨm); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser63/Ser73, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca2+ influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 μM), CU (10 μM), or SP (1 μM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 μM) concentration was efficient in diminishing the iAβ, p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 markers by -50%, -75%, -86%, and -100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 by -69% and -38%, -100% and -62%, -100% and -62%, respectively, these combinations did not alter the iAβ compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca2+ influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAβ-induced ChLN damage in FAD.