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Biotech / Medical : Indications - Neurodegenerative -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (114)	10/4/2004 12:11:38 PM
From: tuck	Respond to of 448

[4,5-dianilinophthalimide: Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule] Published online before print September 23, 2004 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0405941101 OPEN ACCESS ARTICLE Inaugural Article Neuroscience Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule Barbara J. Blanchard, Albert Chen, Leslie M. Rozeboom, Kate A. Stafford, Peter Weigele, and Vernon M. Ingram * Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 30, 2002. Contributed by Vernon M. Ingram, August 13, 2004 The A1-42 peptide that is overproduced in Alzheimer's disease (AD) from a large precursor protein has a normal amino acid sequence but, when liberated, misfolds at neutral pH to form "protofibrils" and fibrils that are rich in -sheets. We find that these protofibrils or fibrils are toxic to certain neuronal cells that carry Ca-permeant -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Disrupting the structure of the A1-42 fibrils and protofibrils might lead to the discovery of molecules that would be very useful in the treatment of AD. A high-throughput screen of a library of >3,000 small molecules with known "biological activity" was set up to find compounds that efficiently decrease the -sheet content of aggregating A1-42. Lead compounds were characterized by using thioflavin T (ThT) as a -sheet assay. The most effective of six compounds found was 4,5-dianilinophthalimide (DAPH) under the following conditions: DAPH at low micromolar concentrations abolishes or greatly reduces previously existing fully formed A1-42 fibrils, producing instead amorphous materials without fibrils but apparently containing some protofibrils and smaller forms. Coincubation of the A1-42 peptide with DAPH produces either amorphous materials or empty fields. Coincubation of DAPH and A1-42 greatly reduces the -sheet content, as measured with ThT fluorescence, and produces a novel fluorescent complex with ThT. When the A1-42 peptide was coincubated with DAPH at very low micromolar concentrations, the neuronal toxicity mentioned above (Ca2+ influx) was eliminated. Clearly, DAPH is a promising candidate for AD therapy.<< Full text PDF here: pnas.org Cheers, Tuck