| First Author | Ueda S | Year | 2023 |
| Journal | FASEB J | Volume | 37 |
| Issue | 11 | Pages | e23252 |
| PubMed ID | 37850918 | Mgi Jnum | J:348873 |
| Mgi Id | MGI:7618913 | Doi | 10.1096/fj.202300837R |
| Citation | Ueda S, et al. (2023) Acute inhibition of AMPA receptors by perampanel reduces amyloid beta-protein levels by suppressing beta-cleavage of APP in Alzheimer's disease models. FASEB J 37(11):e23252 |
| abstractText | Hippocampal hyperexcitability is a promising therapeutic target to prevent Abeta deposition in AD since enhanced neuronal activity promotes presynaptic Abeta 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 Abeta-evoked neuronal hyperexcitability, the acute effects of PER on Abeta metabolism were investigated. A single oral administration of PER rapidly decreased ISF Abeta(40) and Abeta(42) levels in the hippocampus of J20, APP transgenic mice, without affecting the Abeta(40) /Abeta(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 betaCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPbeta levels, a direct byproduct of beta-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Abeta-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Abeta clearance, a gamma-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Abeta, indicating that the acute effect of PER is predominantly on Abeta production. In conclusion, acute treatment of PER reduces Abeta production by suppressing beta-cleavage of amyloid-beta precursor protein effectively, indicating a potential effect of PER against Abeta pathology in AD. |
