AMPA-ergic regulation of amyloid-β levels in an Alzheimer's disease mouse model

Background: Extracellular aggregation of the amyloid-beta (A beta) peptide into toxic multimers is a key event in Alzheimer's disease (AD) pathogenesis. A beta aggregation is concentration-dependent, with higher concentrations of A beta much more likely to form toxic species. The processes that regulate extracellular levels of A beta therefore stand to directly affect AD pathology onset. Studies from our lab and others have demonstrated that synaptic activity is a critical regulator of A beta production through both presynaptic and postsynaptic mechanisms. AMPA receptors (AMPA-Rs), as the most abundant ionotropic glutamate receptors, have the potential to greatly impact A beta levels. Methods: In order to study the role of AMPA-Rs in A beta regulation, we used in vivo microdialysis in an APP/PS1 mouse model to simultaneously deliver AMPA and other treatments while collecting A beta from the interstitial fluid (ISF). Changes in A beta production and clearance along with inflammation were assessed using biochemical approaches. IL-6 deficient mice were utilized to test the role of IL-6 signaling in AMPA-R-mediated regulation of A beta levels. Results: We found that AMPA-R activation decreases in ISF A beta levels in a dose-dependent manner. Moreover, the effect of AMPA treatment involves three distinct pathways. Steady-state activity of AMPA-Rs normally promotes higher ISF A beta. Evoked AMPA-R activity, however, decreases A beta levels by both stimulating glutamatergic transmission and activating downstream NMDA receptor (NMDA-R) signaling and, with extended AMPA treatment, acting independently of NMDA-Rs. Surprisingly, we found this latter, direct AMPA pathway of A beta regulation increases A beta clearance, while A beta production appears to be largely unaffected. Furthermore, the AMPA-dependent decrease is not observed in IL-6 deficient mice, indicating a role for IL-6 signaling in AMPA-R-mediated A beta clearance. Conclusion: Though basal levels of AMPA-R activity promote higher levels of ISF A beta, evoked AMPA-R signaling decreases A beta through both NMDA-R-dependent and -independent pathways. We find that evoked AMPA-R signaling increases clearance of extracellular A beta, at least in part through enhanced IL-6 signaling. These data emphasize that A beta regulation by synaptic activity involves a number of independent pathways that together determine extracellular A beta levels. Understanding how these pathways maintain A beta levels prior to AD pathology may provide insights into disease pathogenesis.