Fernandez-Escamilla AM, Rousseau F, Schymkowitz J, Serrano L.
Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins.
Nat Biotechnol. 2004 Oct;22(10):1302-6.
PubMed.
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.
Comments
University of North Carolina at Chapel Hill
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
View all comments by Kyle Wilcoxhigh-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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