轴突转运障碍致自噬体大量堆积于轴突引发自噬应激,促进阿尔茨海默病(AD)发生发展,且顺、逆向转运分子马达Kinesin和Dynein直接参与自噬体轴突转运,而GSK-3β参与调控分子马达,是AD治疗新靶点。我们研究证实植物化合物Curcumin可抑制GSK-3β,在AD中发挥神经保护作用,同时还发现Curcumin明显减轻AD转基因鼠脑中自噬体在轴突的堆积,并增强Dynein表达。结合前期研究,我们提出:Curcumin通过抑制GSK-3β调控分子马达促进AD自噬体轴突转运以减轻AD自噬应激发挥脑保护作用。本研究利用离体及在体AD模型,先观察Curcumin对自噬体的轴突转运及神经保护作用,再分析该作用是否通过调控顺、逆向转运马达,并进一步探讨Curcumin通过此调控是否依赖于GSK-3β。本课题从一个全新的视角探讨Curcumin多重脑保护作用的分子机制,为防治神经变性疾病提供新策略。

Accumulation of autophagosomes in distal of axon caused by axonal transport disorders induced autophagic stress in Alzheimer's disease (AD) and promoted the development of AD. Both of the anterograde and retrograde motors, kinesin and dynein are directly involved in the transport of autophagosomes. GSK-3β plays a key role in regulation of molecular motors, which is a new therapeutic target for treatment of AD. Our previous studies showed plant compounds Curcumin had neuroprotection in AD via inhibiting GSK-3β, and also found that Curcumin significantly ameliorated the accumulation of autophagosomes and enhanced the expression of dynein. Based on the recent findings, we hypothesize Curcumin ameliorates autophagic stress in AD via regulation of motor-driven axonal transport of autophagosomes by inhibiting GSK-3β. The AD cell models including N2ABP1 cells stably expressing APP695sw and the primary hippocampal neurons from AD transgenic mice, also AD transgenic mouse model will be used in this study. The effects of Curcumin on the axonal transport of autophagosomes and its neuroprotection will be firstly examined. Then, whether the effects of Curcumin are mediated by integrated regulation of anterograde and retrograde motors will be investigated. Furthermore, whether the regulation of axonal transport depends on the inhibition of GSK-3β by Curcumin will be studied. Our project will explore the molecular mechanism of neuroprotection of Curcumin from a new sight and further elucidate the multiple protective mechanisms of Curcumin on prevention and treatment of AD.