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NEUROPHARMACOLOGY

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

Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana (D.K.L, D.C., B.M.); Section on Drug Design and Delivery, Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland (H.W.H., Q.-s.Y., T.U., N.H.G.); Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana (T.U., T.G.); and Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina (K.S.)

Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid -peptide (A), a proteolytic fragment of amyloid 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 A-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and A. 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 A 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. A₄₀ and A₄₂ levels were significantly lowered by posiphen (15 mg/kg) compared with controls. The activities of -, -, and -secretases were assessed in the same brain samples, and -secretase activity was significantly reduced. Posiphen, like phenserine, can lower A via multiple mechanisms and represents an interesting drug candidate for AD treatment.

Address correspondence to: Dr. Debomoy K. Lahiri, Institute of Psychiatric Research, PR-313, Department of Psychiatry, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202. E-mail: dlahiri{at}iupui.edu

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