Activation of distinct synaptic populations regulates extracellular release of ILEI⁄FAM3C and Aβ

Background Previously, we reported a novel role of the secretory protein ILEI (also referred to as FAM3C) in modulation of APP metabolism. ILEI binds to the γ‐secretase complex and destabilizes APP C–terminal fragments (CTFs) to suppress Aβ production without inhibiting γ‐secretase activity. ILEI is localized in the trans– Golgi network and the endocytic vesicles where Aβ is produced from PS1:APP–CTFβ complexes. Synaptosome fractionation analysis further indicated that ILEI is colocalized with APP and the γ‐secretase complex at the synaptic vesicle. In this study, we investigated how activation or suppression of a specific synapse population affects extracellular release of ILEI and Aβ. Method In order to measure ILEI concentration, we first generated monoclonal antibodies against recombinant ILEI and setup sandwich ELISA. ILEI and Aβ concentrations in the interstitial fluid of cerebral cortex of freely moving mice were monitored by microdialysis. Using humanized mutant APP–knockin mice, we examined an effect of selective agonist or antagonist for a specific population of neurotransmitter receptors on ILEI and Aβ secretion. Result Microdialysis study using APP–knockin mice revealed that interstitial fluid concentration of ILEI was fluctuated and roughly parallel with a level of locomotor activity but not with that of Aβ. Reverse dialysis treatment with anesthetics, tetrodotoxin and tetanus toxin markedly decreased both of ILEI and Aβ in the interstitial fluid. On the other hands, treatment with agonist (diazepam) and antagonist (picrotoxin) for GABA A receptor decreased and increased both ILEI and Aβ, respectively. Conclusion Our results suggest that presynaptic ILEI and Aβ are similarly released into the extracellular space in a synaptic activity–dependent manner. Especially, ILEI secretion is largely dependent on GABA A receptor activity.