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...  Read more

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.

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