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In Vitro and Mechan...
In Vitro and Mechanistic Studies of an Antiamyloidogenic Self-Assembled Cyclic D,L-alpha-Peptide Architecture
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Richman, Michal (författare)
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Wilk, Sarah (författare)
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Chemerovski, Marina (författare)
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- Wärmländer, Sebastian K. T. S. (författare)
- Stockholms universitet,Institutionen för biokemi och biofysik
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- Wahlström, Anna (författare)
- Stockholms universitet,Institutionen för biokemi och biofysik
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- Gräslund, Astrid (författare)
- Stockholms universitet,Institutionen för biokemi och biofysik
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Rahimipour, Shai (författare)
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(creator_code:org_t)
- 2013-02-19
- 2013
- Engelska.
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 135:9, s. 3474-3484
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Misfolding of the A beta protein and its subsequent aggregation into toxic oligomers are related to Alzheimer's disease. Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction. Given the significant similarities between amyloids and the architecture of self-assembled cyclic D,L-alpha-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of A beta thereby preventing its aggregation into toxic forms. By screening a focused library of six-residue cyclic D,L-alpha-peptides and optimizing the activity of a lead peptide, we found one cyclic D,L-alpha-peptide (CP-2) that interacts strongly with A beta and inhibits its aggregation. In transmission electron microscopy, optimized thioflavin T and cell survival assays, CP-2 inhibits the formation of A beta aggregates, entirely disassembles preformed aggregated and fibrillar A beta, and protects rat pheochromocytoma PC12 cells from A beta toxicity, without inducing any toxicity by itself. Using various immunoassays, circular dichroism spectroscopy, photoinduced cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE, and NMR, we probed the mechanisms underlying CP-2's antiamyloidogenic activity. NMR spectroscopy indicates that CP-2 interacts with A beta through its self-assembled conformation and induces weak secondary structure in A beta. Upon coincubation, CP-2 changes the aggregation pathway of A beta and alters its oligomer distribution by stabilizing small oligomers (1-3 mers). Our results support studies suggesting that toxic early oligomeric states of A beta may be composed of antiparallel beta-peptide structures and that the interaction of A beta with CP-2 promotes formation of more benign parallel beta-structures. Further studies will show whether these kinds of abiotic cyclic D,L-alpha-peptides are also beneficial as an intervention in related in vivo models.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
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