The Experimental Alzheimer's Disease Drug Posiphen [(+)-Phenserine] Lowers Amyloid-beta Peptide Levels in Cell Culture and Mice

摘要

Major characteristics of Alzheimer's disease (AD) are synaptic loss,cholinergic dysfunction,and abnormal protein depositions in the brain.The amyloid beta-peptide (A beta),a proteolytic fragment of amyloid beta precursor protein (APP),aggregates to form neu-ritic plaques and has a causative role in AD.A present focus of AD research is to develop safe A beta-lowering drugs.A selective acetylcholinesterase inhibitor,phenserine,in current human trials lowers both APP and A beta.Phenserine is dose-limited in animals by its cholinergic actions;its cholinergically inactive enantiomer,posiphen (+)-[phenserine],was assessed.In cultured human neuroblastoma cells,posiphen,like phenserine,dose-and time-dependently lowered APP and A beta levels by reducing the APP synthesis rate.This action translated to an in vivo system.Posiphen administration to mice (7.5-75 mg/kg daily,21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner.A beta_(40) and A beta_(42) levels were significantly lowered by posiphen (>=15 mg/kg) compared with controls.The activities of alpha-,beta-,and gamma-secretases were assessed in the same brain samples,and beta-secretase activity was significantly reduced.Posiphen,like phenserine,can lower A beta via multiple mechanisms and represents an interesting drug candidate for AD treatment.