Identification of novel small molecule inhibitors of amyloid precursor protein synthesis as a route to lower Alzheimer's disease amyloid-β peptide

Tada Utsuki, Qian Sheng Yu, Diane Davidson, Demao Chen, Harold W. Holloway, Arnold Brossi, Kumar Sambamurti, Debomoy K. Lahiri, Nigel H. Greig, Tony Giordano

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Abstract

A wealth of independent research with transgenic mice, antibodies, and vaccines has pointed to a causative role of the amyloid-β peptide (Aβ) in Alzheimer's disease (AD). Based on these and earlier associative studies, Aβ represents a promising target for development of therapeutics focused on AD disease progression. Interestingly, a cholinesterase inhibitor currently in clinical trials, phenserine, has been shown to inhibit production of both amyloid precursor protein (APP) and Aβ. We have shown that this inhibition occurs at the post-transcriptional level with a specific blocking of the synthesis of APP relative to total protein synthesis (Shaw et al., 2001). However, the dose of phenserine necessary to block APP production is far higher than that needed to elicit its anticholinesterase activity, and it is these latter actions that are dose limiting in vivo. The focus of this study was to screen 144 analogs of phenserine to identify additional small molecules that inhibit APP protein synthesis, and thereby Aβ production, without possessing potent acetylcholinesterase (AChE) inhibitory activity. An enzyme-linked immunosorbent assay was used to identify analogs capable of suppressing APP production following treatment of human neuroblastoma cells with 20 μM of compound. Eight analogs were capable of dose dependently reducing APP and Aβ production without causing cell toxicity in further studies. Several of these analogs had little to no AChE activities. Translation of APP and Aβ actions to mice was demonstrated with one agent. They thus represent interesting lead molecules for assessment in animal models, to define their tolerance and utility as potential AD therapeutics.

Original languageEnglish (US)
Pages (from-to)855-862
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume318
Issue number2
DOIs
StatePublished - Jul 20 2006

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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