摘要
Neuronal amyloid-beta (A beta) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD). The conformation and toxicity of A beta are regulated by lipids on the plasma membrane. Previously, we found downregulation of Rolling Blackout (RBO) or phosphatidylinositol-4-kinase type III alpha (PI4KIII1 alpha) reduces neuronal A beta accumulation and associated neural deficits in a Drosophila model expressing A beta(42) . In mammals, the homologs of RBO and PI4KIII alpha 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 A beta accumulation and associated synaptic and motor defects as well as premature death in A beta(42) -expressing flies, while overexpression of TTC7 and Hyccin produced the opposite effect. These results, together with our previous study, demonstrate that RBO/TTC7/PI4KIII alpha/Hyccin regulate neuronal A beta accumulation and associated neural deficits in the Drosophila model, further supporting the RBO/Efr3-PI4KIII alpha complex as a potential therapeutic target for AD.
