Latrepirdine (Dimebon™) Enhances Autophagy and Reduces Intracellular GFP-Aβ42 Levels in Yeast
Latrepirdine (Dimebon™) Enhances Autophagy and Reduces Intracellular GFP-Aβ42 Levels in Yeast
复制标题
DOI：
10.3233/jad-2012-120178
复制
发表时间：
2012-01-01
影响因子：
4
通讯作者：
Martins, Ralph N.
中科院分区：
文献类型：
--
作者：
Bharadwaj, Prashant R.;Verdile, Giuseppe;Martins, Ralph N.
Latrepirdine（Dimebon（TM））是一种抗组胺剂，在以聚集或错误折叠的蛋白质的积累为特征的神经变性疾病如阿尔茨海默病（AD）的试验中显示出一些益处，并且已显示出促进体内α-突触核蛋白聚集体的去除。去除聚集或错误折叠的蛋白质的重要途径是自噬-溶酶体途径，其与AD发病机制有关，并且增强该途径已被证明在AD和其他蛋白质病中具有治疗潜力。在这里，我们使用酵母模型，酿酒酵母，研究拉曲匹定是否可以增强自噬和降低淀粉样蛋白β（A β）（42）聚集体的水平。拉曲匹定显示上调酵母液泡（溶酶体）活性，并促进自噬标记物（Atg 8）转运至液泡。使用体外绿色荧光蛋白（GFP）标记的A β酵母表达系统，我们研究了拉瑞普定增强的自噬是否与细胞内GFP-A β水平的降低相关（42）。与不聚集的GFP和GFP-A β（42）（19：34）的弥散胞质模式相比，GFP-A β（42）定位成点状模式。在自噬缺陷突变体（Atg8 Delta）中，GFP-A β（42）显示出更弥散的胞质定位，反映了该突变体不能螯合GFP-A β（42）。与雷帕霉素类似，我们观察到，与Atg8 Delta突变体相比，latrepirdine显著降低了野生型中的GFP-A β（42）。此外，拉曲匹定治疗减弱了野生型细胞中A β（42）诱导的毒性，但在Atg 8 Delta突变体中却没有减弱。总之，我们的研究结果为latrepirdine诱导自噬和降低GFP-A β细胞内水平的新作用机制提供了证据（42）。
Latrepirdine (Dimebon (TM)), an anti-histamine, has shown some benefits in trials of neurodegenerative diseases characterized by accumulation of aggregated or misfolded protein such as Alzheimer's disease (AD) and has been shown to promote the removal of alpha-synuclein protein aggregates in vivo. An important pathway for removal of aggregated or misfolded proteins is the autophagy-lysosomal pathway, which has been implicated in AD pathogenesis, and enhancing this pathway has been shown to have therapeutic potential in AD and other proteinopathies. Here we use a yeast model, Saccharomyces cerevisiae, to investigate whether latrepirdine can enhance autophagy and reduce levels of amyloid-beta (A beta)(42) aggregates. Latrepirdine was shown to upregulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Using an in vitro green fluorescent protein (GFP) tagged A beta yeast expression system, we investigated whether latrepirdine-enhanced autophagy was associated with a reduction in levels of intracellular GFP-A beta(42). GFP-A beta(42) was localized into punctate patterns compared to the diffuse cytosolic pattern of GFP and the GFP-A beta(42) (19 : 34), which does not aggregate. In the autophagy deficient mutant (Atg8 Delta), GFP-A beta(42) showed a more diffuse cytosolic localization, reflecting the inability of this mutant to sequester GFP-A beta(42). Similar to rapamycin, we observed that latrepirdine significantly reduced GFP-A beta(42) in wild-type compared to the Atg8 Delta mutant. Further, latrepirdine treatment attenuated A beta(42)-induced toxicity in wild-type cells but not in the Atg8 Delta mutant. Together, our findings provide evidence for a novel mechanism of action for latrepirdine in inducing autophagy and reducing intracellular levels of GFP-A beta(42).