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

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

Research output: Contribution to journalArticle

90 Citations (Scopus)

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

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Amyloid
Alzheimer Disease
Cell Culture Techniques
Peptides
Serum Amyloid A Protein
Pharmaceutical Preparations
Amyloid beta-Protein Precursor
Amyloid Precursor Protein Secretases
Cholinergic Agents
phenserine
Cholinesterase Inhibitors
Amyloid Plaques
Brain
Neuroblastoma
Research

ASJC Scopus subject areas

  • Pharmacology

Cite this

The experimental Alzheimer's Disease drug posiphen [(+)-phenserine] lowers amyloid-β peptide levels in cell culture and mice. / Lahiri, Debomoy; Chen, DeMao; Maloney, Bryan; Holloway, Harold W.; Yu, Qian Sheng; Utsuki, Tada; Giordano, Tony; Sambamurti, Kumar; Greig, Nigel H.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 320, No. 1, 2007, p. 386-396.

Research output: Contribution to journalArticle

Lahiri, Debomoy ; Chen, DeMao ; Maloney, Bryan ; Holloway, Harold W. ; Yu, Qian Sheng ; Utsuki, Tada ; Giordano, Tony ; Sambamurti, Kumar ; Greig, Nigel H. / The experimental Alzheimer's Disease drug posiphen [(+)-phenserine] lowers amyloid-β peptide levels in cell culture and mice. In: Journal of Pharmacology and Experimental Therapeutics. 2007 ; Vol. 320, No. 1. pp. 386-396.
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