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

Debomoy K. Lahiri, De Mao Chen, Bryan Maloney, Harold W. Holloway, Qian Sheng Yu, Tada Utsuki, Tony Giordano, Kumar Sambamurti, Nigel H. Greig

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

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. Aβ40 and Aβ42 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.

Original languageEnglish (US)
Pages (from-to)386-396
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume320
Issue number1
DOIs
StatePublished - Jan 5 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'The experimental Alzheimer's Disease drug posiphen [(+)-phenserine] lowers amyloid-β peptide levels in cell culture and mice'. Together they form a unique fingerprint.

  • Cite this