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

Abstract

BackgroundExtracellular aggregation of the amyloid-β (Aβ) peptide into toxic multimers is a key event in Alzheimer’s disease (AD) pathogenesis. Aβ aggregation is concentration-dependent, with higher concentrations of Aβ much more likely to form toxic species. The processes that regulate extracellular levels of Aβ therefore stand to directly affect AD pathology onset. Studies from our lab and others have demonstrated that synaptic activity is a critical regulator of Aβ production through both presynaptic and postsynaptic mechanisms. AMPA receptors (AMPA-Rs), as the most abundant ionotropic glutamate receptors, have the potential to greatly impact Aβ levels.MethodsIn order to study the role of AMPA-Rs in Aβ regulation, we used in vivo microdialysis in an APP/PS1 mouse model to simultaneously deliver AMPA and other treatments while collecting Aβ from the interstitial fluid (ISF). Changes in Aβ 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 Aβ levels.ResultsWe found that AMPA-R activation decreases in ISF Aβ 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 Aβ. Evoked AMPA-R activity, however, decreases Aβ 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 Aβ regulation increases Aβ clearance, while Aβ 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 Aβ clearance.ConclusionThough basal levels of AMPA-R activity promote higher levels of ISF Aβ, evoked AMPA-R signaling decreases Aβ through both NMDA-R-dependent and -independent pathways. We find that evoked AMPA-R signaling increases clearance of extracellular Aβ, at least in part through enhanced IL-6 signaling. These data emphasize that Aβ regulation by synaptic activity involves a number of independent pathways that together determine extracellular Aβ levels. Understanding how these pathways maintain Aβ levels prior to AD pathology may provide insights into disease pathogenesis.

RAB39B Deficiency Impairs Learning and Memory Partially Through Compromising Autophagy

“…AMPA receptors and NMDA receptors play crucial roles in synaptic function and memory formation ( Scannevin and Huganir, 2000 ; Hettinger et al, 2018 ; Hanada, 2020 ). To characterize potential differences of the two receptors in Rab39b KO mice, we measured NMDA/AMPA receptor response ratios and evoked AMPA excitatory postsynaptic currents (AMPA-eEPSCs) in hippocampal CA1 neurons of WT and Rab39b KO mice.…”

Chinese Herbal Medicine Interventions in Neurological Disorder Therapeutics by Regulating Glutamate Signaling

“…In the early stages of neurological disease, glutamate-induced excitotoxicity contributes to neuronal death by overstimulating glutamate receptors, which subsequently results in Ca 2+ overload. However, the amyloid plaques, phosphorylated tau, and α-synuclein may trigger synaptic loss and abnormal distribution of glutamate receptors [ 67 ]. As a result, the disruption of the normal glutamate signaling via glutamate receptors is implicated in a wide range of neurologic diseases [ 30 , 68 , 69 ].…”

Amyloid, APP, and Electrical Activity of the Brain

“…A study on mice overexpressing Aβ showed that its detrimental effect on synapses requires the presence of the AMPAR subunit GluA3 (Reinders and others 2016). On the other hand, AMPAR activation was shown to increase the clearance of Aβ in a dose-dependent manner, thus decreasing its extracellular levels (Hettinger and others 2018). Simultaneously, it promotes non-amyloidogenic cleavage of APP (Hoey and others 2013).…”