Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Laboratory of Molecular Neurobiology, School of Life Sciences, Shanghai University, Shanghai, China.
J Alzheimers Dis. 2018;65(3):1001-1010. doi: 10.3233/JAD-170907.
Neuronal amyloid-β (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD). The conformation and toxicity of Aβ are regulated by lipids on the plasma membrane. Previously, we found downregulation of Rolling Blackout (RBO) or phosphatidylinositol-4-kinase type IIIα (PI4KIIIα) reduces neuronal Aβ accumulation and associated neural deficits in a Drosophila model expressing Aβ42. In mammals, the homologs of RBO and PI4KIIIα were reported to form a plasma membrane-localized complex with a scaffold protein TTC7 and cytosolic protein Hyccin/FAM126A to tightly control the plasmalemmal level of phosphatidylinositol-4-phosphate. Here, we show genetic downregulation of Drosophila TTC7 and Hyccin also reduces neuronal Aβ accumulation and associated synaptic and motor defects as well as premature death in Aβ42-expressing flies, while overexpression of TTC7 and Hyccin produced the opposite effect. These results, together with our previous study, demonstrate that RBO/TTC7/PI4KIIIα/Hyccin regulate neuronal Aβ accumulation and associated neural deficits in the Drosophila model, further supporting the RBO/Efr3-PI4KIIIα complex as a potential therapeutic target for AD.
神经元淀粉样蛋白-β（Aβ）的积累在阿尔茨海默病（AD）的发病机制中起着重要作用。Aβ的构象和毒性受质膜上脂质的调节。先前，我们发现下调 Rolling Blackout（RBO）或磷脂酰肌醇-4-激酶 IIIα（PI4KIIIα）可减少果蝇模型中表达 Aβ42 的神经元 Aβ积累和相关的神经缺陷。在哺乳动物中，RBO 和 PI4KIIIα 的同源物被报道与支架蛋白 TTC7 和胞质蛋白 Hyccin/FAM126A 形成质膜定位复合物，以紧密控制磷脂酰肌醇-4-磷酸的质膜水平。在这里，我们表明 Drosophila TTC7 和 Hyccin 的遗传下调也可减少神经元 Aβ积累以及相关的突触和运动缺陷以及 Aβ42 表达果蝇的过早死亡，而过表达 TTC7 和 Hyccin 则产生相反的效果。这些结果与我们之前的研究一起表明，RBO/TTC7/PI4KIIIα/Hyccin 可调节果蝇模型中神经元 Aβ的积累以及相关的神经缺陷，进一步支持 RBO/Efr3-PI4KIIIα 复合物作为 AD 的潜在治疗靶标。
