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Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity via specific interactions with its histidine residues

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Abstract

The self-assembly of Aβ to β-sheet-rich neurotoxic oligomers is a main pathological event leading to Alzheimer's disease (AD). Selective targeting of Aβ oligomers without affecting other functional proteins is therefore an attractive approach to prevent the disease and its progression. In this study, we report that photodynamic treatment of Aβ in the presence of catalytic amounts of chlorin e6 can selectively damage Aβ and inhibit its aggregation and toxicity. Chlorin e6 also reversed the amyloid aggregation process in the dark by binding its soluble and low molecular weight oligomers, as shown by thioflavin T (ThT) fluorescence and photoinduced cross-linking of unmodified protein (PICUP) methods. Using HSQC NMR spectroscopy, ThT assays, amino acid analysis, SDS/PAGE, and EPR spectroscopy, we show that catalytic amounts of photoexcited chlorin e6 selectively damage the Aβ histidine residues H6, H13, and H14, and induce Aβ cross-linking by generating singlet oxygen. In contrast, photoexcited chlorin e6 was unable to cross-link ubiquitin and α-synuclein, demonstrating its high selectivity for Aβ. By binding to the Aβ histidine residues, catalytic amounts of chlorin e6 can also inhibit the Cu2+-induced aggregation and toxicity in darkness, while at stoichiometric amounts it acts as a chelator to reduce the amount of free Cu2+. This study demonstrates the great potential of chlorin e6 as a multifunctional agent for treatment of AD, and shows that the three N-terminal Aβ histidine residues are a suitable target for Aβ-specific drugs.

Graphical abstract: Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity via specific interactions with its histidine residues

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Publication details

The article was received on 03 May 2018, accepted on 03 Oct 2018 and first published on 03 Oct 2018


Article type: Edge Article
DOI: 10.1039/C8SC01992D
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY-NC license
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    Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity via specific interactions with its histidine residues

    G. Leshem, M. Richman, E. Lisniansky, M. Antman-Passig, M. Habashi, A. Gräslund, S. K. T. S. Wärmländer and S. Rahimipour, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C8SC01992D

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