Acute inhibition of AMPA receptors by perampanel reduces amyloid ß-protein levels by suppressing ß-cleavage of APP in Alzheimer's disease models.

Hippocampal hyperexcitability is a promising therapeutic target to prevent Aß deposition in AD since enhanced neuronal activity promotes presynaptic Aß production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aß-evoked neuronal hyperexcitability, the acute effects of PER on Aß metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aß40 and Aß42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aß40 /Aß42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP ßCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPß levels, a direct byproduct of ß-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aß-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aß clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aß, indicating that the acute effect of PER is predominantly on Aß production. In conclusion, acute treatment of PER reduces Aß production by suppressing ß-cleavage of amyloid-ß precursor protein effectively, indicating a potential effect of PER against Aß pathology in AD.