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Download fileConcentration Dependent Cu2+ Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide†
journal contribution
posted on 13.03.2007, 00:00 authored by David P. Smith, Giuseppe D. Ciccotosto, Deborah J. Tew, Michelle T. Fodero-Tavoletti, Timothy Johanssen, Colin L. Masters, Kevin J. Barnham, Roberto CappaiThe Amyloid β peptide (Aβ) of Alzheimer's diseases (AD) is closely linked to the progressive
cognitive decline associated with the disease. Cu2+ ions can induce the de novo aggregation of the Aβ
peptide into non-amyloidogenic aggregates and the production of a toxic species. The mechanism by
which Cu2+ mediates the change from amyloid material toward Cu2+ induced aggregates is poorly defined.
Here we demonstrate that the aggregation state of Aβ1−42 at neutral pH is governed by the Cu2+:peptide
molar ratio. By probing amyloid content and total aggregation, we observed a distinct Cu2+ switching
effect centered at equimolar Cu2+:peptide ratios. At sub-equimolar Cu2+:peptide molar ratios, Aβ1−42
forms thioflavin-T reactive amyloid; conversely, at supra-equimolar Cu2+:peptide molar ratios, Aβ1−42
forms both small spherical oligomers approximately 10−20 nm in size and large amorphous aggregates.
We demonstrate that these insoluble aggregates form spontaneously via a soluble species without the
presence of an observable lag phase. In seeding experiments, the Cu2+ induced aggregates were unable
to influence fibril formation or convert into fibrillar material. Aged Cu2+ induced aggregates are toxic
when compared to Aβ1−42 aged in the absence of Cu2+. Importantly, the formation of dityrosine
crosslinked Aβ, by the oxidative modification of the peptide, only occurs at equimolar molar ratios and
above. The formation of dityrosine adducts occurs following the initiation of aggregation and hence does
not drive the formation of the Cu2+ induced aggregates. These results define the role Cu2+ plays in
modulating the aggregation state and toxicity of Aβ1−42.