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.
Footnotes
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This work was supported in part by the National Institutes of Health (R01 Grants AG18379 and AG18884), by the Intramural Research Program of National Institute on Aging, by the Alzheimer's Association (Zenith Award), and by Axonyx, Inc.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.112102.
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ABBREVIATIONS: AD, Alzheimer's disease; τ, microtubule-associated protein τ; Aβ, amyloid-β peptide; APP, Aβ precursor protein; CTF, C-terminal fragment; AChE, acetylcholinesterase; UTR, untranslated region; IL, interleukin; posiphen, (+)-phenserine; DMEM, Dulbecco's modified Eagle's medium; ELISA, enzyme-linked immunosorbent assay; TCA, trichloroacetic acid; PCR, polymerase chain reaction; BChE, butyrylcholinesterase; FU, fluorescence unit(s).
- Received August 7, 2006.
- Accepted September 25, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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