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

J Pharmacol Exp Ther. 2007 Jan;320(1):386-96. doi: 10.1124/jpet.106.112102. Epub 2006 Sep 26.

Abstract

Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid beta-peptide (Abeta), 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 Abeta-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and Abeta. 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 Abeta 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. Abeta40 and Abeta42 levels were significantly lowered by posiphen (> or =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 Abeta via multiple mechanisms and represents an interesting drug candidate for AD treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / analysis*
  • Amyloid beta-Protein Precursor / analysis
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Cell Line, Tumor
  • Cerebral Cortex / chemistry
  • Cerebral Cortex / drug effects
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Physostigmine / analogs & derivatives*
  • Physostigmine / pharmacology
  • RNA, Messenger / analysis
  • Stereoisomerism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Cholinesterase Inhibitors
  • RNA, Messenger
  • Physostigmine
  • Amyloid Precursor Protein Secretases
  • phenserine