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...