. Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule. Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14326-32. PubMed.

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  1. By a high-throughput screen using >3,000 small molecules, the authors found that 4,5-dianilinophthalimide (DAPH) inhibits the aggregation and neuronal toxicity associated with the Aβ1-42 peptide from the amyloid precursor protein, APP. After showing that the Aβ1-42 peptide used in their experiments is able to form ordered aggregates upon incubation and that these same aggregates are able to affect transmembrane Ca2+ flux via an interaction with the Ca-permeant AMPA receptor, the investigators present evidence indicating that DAPH is able to prevent both of these phenomena. Electron microscopy and thioflavin T fluorescence data show that DAPH not only prevents the growth of Aβ1-42 fibrils from peptides, but also reverses the formation of preformed Aβ amyloid fibrils. A shift in the thioflavin T emission peak in the presence of DAPH suggests that the small molecule is inducing a change in the β structure in the aggregates to a form which no longer can aggregate or interact with those neurons containing AMPA Ca2+ receptors.

    The Aβ1-42 aggregate-induced Ca2+ influx into neuronal cells was found to be dependent on the Aβ1-42 peptide concentration and the length of preincubation to form aggregates. The most dramatic effect on cytosolic Ca2+ levels occurs after 24 hours of preincubation, at which point Aβ protofibrils are formed. The authors use a fluorescent dye sensitive to cytosolic Ca2+ levels to show that these aggregates cannot cause Ca2+ influx in the presence of two specific inhibitors to the AMPA receptor. The same restriction of Ca2+ influx was reproduced using DAPH at concentrations similar to the Aβ concentration.

    Taken together, these findings suggest that by interfering with the β structure of high-order Aβ aggregates, it is possible to ameliorate their neuronal toxicity, thus highlighting the potential for using small molecules to treat Alzheimer disease and diseases of protein misfolding and aggregation.

    View all comments by Kyle Wilcox

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