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

Hippocampal hyperexcitability is a promising therapeutic target to prevent A beta deposition in AD since enhanced neuronal activity promotes presynaptic A beta 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 A beta-evoked neuronal hyperexcitability, the acute effects of PER on A beta metabolism were investigated. A single oral administration of PER rapidly decreased ISF A beta(40) and A beta(42) levels in the hippocampus of J20, APP transgenic mice, without affecting the A beta(40)/A beta(42) ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP beta CTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPP beta levels, a direct byproduct of beta-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric A beta-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF A beta clearance, a gamma-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF A beta, indicating that the acute effect of PER is predominantly on A beta production. In conclusion, acute treatment of PER reduces A beta production by suppressing beta-cleavage of amyloid-beta precursor protein effectively, indicating a potential effect of PER against A beta pathology in AD.