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

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.

• Authors: Debomoy K Lahiri, DeMao Chen, Bryan Maloney, Harold W Holloway, Qian-sheng Yu, Tada Utsuki, Tony Giordano, Kumar Sambamurti, Nigel H Greig
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 320 Issue 1 Pg. 386-96 (Jan 2007) ISSN: 0022-3565 [Print] United States
• PMID: 17003227 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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