Cobalt(III) Schiff base complexes stabilize non-fibrillar amyloid-β aggregates with reduced toxicity

Kaleigh F. Roberts, Christopher R. Brue, Anna Preston, Damonick Baxter, Emma Herzog, Eleni Varelas, Thomas J. Meade*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The aggregation of amyloid-β (Aβ) is believed to be foundational to the pathogenesis of Alzheimer's disease (AD). In vitro aggregation kinetics have been shown to correlate with rates of disease progression in both AD patients and animal models, thus proving to be a useful metric for testing Aβ-targeted therapeutics. Here we present evidence of cobalt(III) Schiff base complex ([Co(acetylacetonate)(NH3)2]Cl; Co(III)-sb) modulation of Aβ aggregation kinetics by a variety of complementary techniques. These include Thioflavin T (ThT) fluorescence, circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), and atomic force microscopy (AFM). Our data was fitted to kinetic rate laws using a mathematical model developed by Knowles et al. in order to extract mechanistic information about the effect of Co(III)-sb on aggregation kinetics. Our analysis revealed that Co(III)-sb alters Aβ aggregation by decreasing the polymerization rate and increasing the nucleation rate, suggesting that Co(III)-sb causes Aβ to rapidly stabilize oligomeric species with reduced elongation into mature fibrils. This result was corroborated by TEM and AFM of Aβ aggregates in vitro. We also demonstrate that Aβ aggregate mixtures produced in the presence of Co(III)-sb exhibit decreased cytotoxicity compared to untreated samples.

Original languageEnglish (US)
Article number111265
JournalJournal of Inorganic Biochemistry
Volume213
DOIs
StatePublished - Dec 2020

Keywords

  • Aggregation
  • Amyloid-β
  • Cobalt (III)
  • Fibrillar
  • Schiff base complexes
  • Toxicity

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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