Downregulation of RBO-PI4KIIIα Facilitates Aβ₄₂ Secretion and Ameliorates Neural Deficits in Aβ₄₂-Expressing Drosophila.

Phosphoinositides and their metabolizing enzymes are involved in Aβ₄₂ metabolism and Alzheimer's disease pathogenesis. In yeast and mammals, Eighty-five requiring 3 (EFR3), whose Drosophila homolog is Rolling Blackout (RBO), forms a plasma membrane-localized protein complex with phosphatidylinositol-4-kinase Type IIIα (PI4KIIIα) and a scaffold protein to tightly control the level of plasmalemmal phosphatidylinositol-4-phosphate (PI₄P). Here, we report that RBO binds to Drosophila PI4KIIIα, and that in an Aβ₄₂-expressing Drosophila model, separate genetic reduction of PI4KIIIα and RBO, or pharmacological inhibition of PI4KIIIα ameliorated synaptic transmission deficit, climbing ability decline, premature death, and reduced neuronal accumulation of Aβ₄₂ Moreover, we found that RBO-PI4KIIIa downregulation increased neuronal Aβ₄₂ release and that PI4P facilitated the assembly or oligomerization of Aβ₄₂ in/on liposomes. These results indicate that RBO-PI4KIIIa downregulation facilitates neuronal Aβ₄₂ release and consequently reduces neuronal Aβ₄₂ accumulation likely via decreasing Aβ₄₂ assembly in/on plasma membrane. This study suggests the RBO-PI4KIIIα complex as a potential therapeutic target and PI4KIIIα inhibitors as drug candidates for Alzheimer's disease treatment.SIGNIFICANCE Phosphoinositides and their metabolizing enzymes are involved in Aβ₄₂ metabolism and Alzheimer's disease pathogenesis. Here, in an Aβ₄₂-expressing Drosophila model, we discovered and studied the beneficial role of downregulating RBO or its interacting protein PI4KIIIα-a protein that tightly controls the plasmalemmal level of PI₄P-against the defects caused by Aβ₄₂ expression. Mechanistically, RBO-PI4KIIIα downregulation reduced neuronal Aβ₄₂ accumulation, and interestingly increased neuronal Aβ₄₂ release. This study suggests the RBO-PI4KIIIα complex as a novel therapeutic target, and PI4KIIIα inhibitors as new drug candidates.