ATG14调节自噬流对Aβ的作用及功能意义

Aβ产生和降解代谢失衡是引起阿尔茨海默病（AD）的重要原因，自噬障碍与Aβ代谢失衡密切相关。由于自噬过度激活，自噬体与溶酶体融合障碍或溶酶体功能受抑制，导致自噬体聚集，Aβ产生增多，Aβ通过自噬溶酶体途径清除减少。因此，调节可激活自噬并促进自噬体与溶酶体融合的关键因子，可能达到平衡Aβ代谢的目的。最近研究证实：自噬相关基因14（ATG14）可激活自噬，并促进自噬体和內吞溶酶体膜的融合。课题组前期研究发现AD模型小鼠脑内ATG14的表达随年龄增加而减少，可能与Aβ代谢障碍密切相关。本课题拟观察AD模型小鼠与自噬流模型小鼠杂交的多转基因小鼠脑内ATG14与自噬流的动态变化以及与Aβ的关系；经抑制和上调ATG14表达后，观察稳定表达淀粉样前体蛋白的细胞株以及模型小鼠脑内自噬流、Aβ的变化及小鼠行为学改变。本项目期望阐明ATG14对Aβ的作用及功能意义，寻找以调节自噬为目标的AD治疗新靶点。

The imbalance of the production and degradation of Aβin the brain is an important cause of Alzheimer's disease (AD), and autophagy is closely related to Aβmetabolism. The excessive activation of autophagy, autophagosome and lysosome fusion disorder or inhibition of lysosomal function may lead to the accumulation of autophagosomes. Abnormal increase of autophagosome is thought to be the source of Aβ. Due to obstruction of autophagy flow, the degradation of Aβ by autophagy - lysosome pathway is reduced. Therefore, it is possible to find the key factors that activate autophagy, and promote the fusion of autophagosome and lysosome, which may regulate the formation and degradation of Aβ. Recent studies have confirmed that autophagy related gene 14 (ATG14) can activate autophagy, and promote the fusion of autophagy and lysosomal membrane. However, the role of ATG14 in AD has not been reported. Previous studies of our group found that the expression of ATG14 in the brain of AD model mice was significantly decrease with increasing age, which may be related to Aβ metabolic disorders. In this study, the APP/PS1 double transgenic AD model mice and the RFP-GFP-LC3 autophagy flow model mice were hybridized to get multi transgenic mice as animal models, then we further observe the dynamic change of ATG14 expression and autophagy flux on the model mice. After transfection with ATG14 or ATG14-siRNA plasmid, observe autophagy flux and Aβ in 20E2 cell line with stable expression of Amyloid precursor protein, as well as behavioral change of mice model. This study aims to elucidate the role and functional implication of ATG14 on Aβ, search for new targets for the treatment of AD with the aim of regulating autophagy flow.