Extracellular Release Of Ilei/Fam3c And Amyloid-Beta Is Associated With The Activation Of Distinct Synapse Subpopulations

Background: Brain amyloid-beta (A beta) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and A beta deposition in Alzheimer's disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for A beta generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous A beta suppressor.Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on A beta production in the brain.Methods: ILEI and A beta levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human A beta precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA.Results: Extracellular release of ILEI and A beta was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and A beta revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of A beta levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and A beta levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of A beta and were reduced in AD and mild cognitive impairment.Conclusion: ILEI and A beta are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates A beta production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain A beta.