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Photoactive chlorin...
Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity via specific interactions with its histidine residues
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Leshem, Guy (author)
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Richman, Michal (author)
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Lisniansky, Elvira (author)
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Antman-Passig, Merav (author)
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Habashi, Maram (author)
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- Gräslund, Astrid (author)
- Stockholms universitet,Institutionen för biokemi och biofysik
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- Wärmländer, Sebastian K. T. S. (author)
- Stockholms universitet,Institutionen för biokemi och biofysik
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Rahimipour, Shai (author)
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(creator_code:org_t)
- 2019
- 2019
- English.
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In: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6520 .- 2041-6539. ; 10:1, s. 208-217
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https://doi.org/10.1...
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https://pubs.rsc.org...
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https://urn.kb.se/re...
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Abstract
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- The self-assembly of A to -sheet-rich neurotoxic oligomers is a main pathological event leading to Alzheimer's disease (AD). Selective targeting of A 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 A in the presence of catalytic amounts of chlorin e6 can selectively damage A 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 A histidine residues H6, H13, and H14, and induce A cross-linking by generating singlet oxygen. In contrast, photoexcited chlorin e6 was unable to cross-link ubiquitin and -synuclein, demonstrating its high selectivity for A. By binding to the A 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 A histidine residues are a suitable target for A-specific drugs.
Subject headings
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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