Affiliations: [a]
Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| [b]
Laboratory of Molecular Neurobiology, School of Life Sciences, Shanghai University, Shanghai, China
| [c]
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| [d]
Department of Neurology, Xinhua Hospital Chongming Branch Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| [e]
Sino-Danish College, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| [f]
Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
Correspondence:
[*]
Correspondence to: Fu-De Huang, Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 201210, China. Tel.: +86 21 20350962; E-mail: huangfd@sari.ac.cn.
Note: [1] These authors contributed equally to this work.
Abstract: 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.
