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

• Published in: The Journal of pharmacology and experimental therapeutics 2007-01, Vol.320 (1), p.386
• Main Authors: Debomoy K. Lahiri, DeMao Chen, Bryan Maloney, Harold W. Holloway, Qian-sheng Yu, Tada Utsuki, Tony Giordano, Kumar Sambamurti, Nigel H. Greig
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.106.112102

Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid β-peptide (Aβ), a proteolytic fragment of amyloid β 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 Aβ-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and Aβ. 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 Aβ 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. Aβ 40 and Aβ 42 levels were significantly lowered by posiphen (≥15 mg/kg) compared with controls. The activities of α-, β-, and γ-secretases were assessed in the same brain samples, and β-secretase activity was significantly reduced. Posiphen, like phenserine, can lower Aβ via multiple mechanisms and represents an interesting drug candidate for AD treatment.