The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-β peptide levels in cell culture and mice

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 neuritic 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.