Downregulation of RBO-PI4KIIIα Facilitates Aβ Secretion and Ameliorates Neural Deficits in Aβ-Expressing

Phosphoinositides and their metabolizing enzymes are involved in Aβ metabolism and Alzheimer's disease pathogenesis. In yeast and mammals, Eighty-five requiring 3 (EFR3), whose 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 (PIP). Here, we report that RBO binds to PI4KIIIα, and that in an Aβ-expressing 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 Aβ Moreover, we found that RBO-PI4KIIIa downregulation increased neuronal Aβ release and that PI4P facilitated the assembly or oligomerization of Aβ in/on liposomes. These results indicate that RBO-PI4KIIIa downregulation facilitates neuronal Aβ release and consequently reduces neuronal Aβ accumulation likely via decreasing Aβ 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. Phosphoinositides and their metabolizing enzymes are involved in Aβ metabolism and Alzheimer's disease pathogenesis. Here, in an Aβ-expressing 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 PIP-against the defects caused by Aβ expression. Mechanistically, RBO-PI4KIIIα downregulation reduced neuronal Aβ accumulation, and interestingly increased neuronal Aβ release. This study suggests the RBO-PI4KIIIα complex as a novel therapeutic target, and PI4KIIIα inhibitors as new drug candidates.