Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid β-protein fibrils

Masuda, Yuichi; Fukuchi, Masashi; Yatagawa, Tatsuya; Tada, Masato; Takeda, Kazuyuki; Irie, Kazuhiro; Akagi, Ken‐ichi; Monobe, Youko; Imazawa, Takayoshi; Takegoshi, K.

doi:10.1016/j.bmc.2011.08.052

Cited by 85 publications

(80 citation statements)

References 75 publications

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“…A recent ssNMR study by Masuda et al (38) has shown that curcumin interacts with the residues from 17 to 21, as well as with residue 12 present in the N-terminal ␤-sheet. Masuda et al (38) postulate that curcumin targets the C-terminal ␤-sheet in a nonspecific fashion.…”

Section: Resultsmentioning

confidence: 99%

“…Masuda et al (38) postulate that curcumin targets the C-terminal ␤-sheet in a nonspecific fashion. Our results substantiate this speculation with three amino acids in this region, namely Leu-34, Val-36, and Gly-38, undergoing either structural reorganization or population redistribution between different conformers in the presence of curcumin.…”

Section: Resultsmentioning

confidence: 99%

“…This discrepancy most likely has its origin in different way these studies have been performed. Masuda et al (38) incubated curcumin with preformed fibrils, whereas we precipitated A␤ 42 from the solution in the presence of curcumin. In a nut shell, curcumin does target the ␤-sheet-rich regions of A␤ 42 , but these are not the only regions affected by it, as shown by our results.…”

Section: Resultsmentioning

confidence: 99%

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Curcumin Alters the Salt Bridge-containing Turn Region in Amyloid β(1–42) Aggregates

Mithu

Sarkar

Bhowmik

et al. 2014

Journal of Biological Chemistry

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Background: Curcumin reduces the risk of Alzheimer disease via an unknown mechanism. Results: Curcumin-incubated A␤ 42 aggregates retain the hairpin architecture but have disruptions in the turn region (surprising similarity with Zn 2ϩ incubation). Conclusion: Salt bridge-containing turn region is a major determinant of morphology and toxicity. Significance: Identification of crucial structural changes provides a checkpoint for developing effective AD therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Curcumin Alters the Salt Bridge-containing Turn Region in Amyloid β(1–42) Aggregates

Mithu

Sarkar

Bhowmik

et al. 2014

Journal of Biological Chemistry

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“…This means that, in A␤ protofibrils, Ile-31 and Glu-22 are in close proximity (Ͻ6 -7 Å), which is observable by 13 C- 13 C correlation spectroscopy (32). The cross-peaks between the other carbons of these two amino acids (including the cross-peak Glu-22 C␣-Ile-31 C␣) are weaker and only sparsely above the noise level, even when using covariance NMR processing, which is known to enhance small cross-peaks (33). For comparison, the standard Fourier transform-processed two-dimensional NMR spectrum is shown in supplemental Fig.…”

Section: Fig 2 Shows Characteristicmentioning

confidence: 98%

Solid-state NMR Reveals a Close Structural Relationship between Amyloid-β Protofibrils and Oligomers

Scheidt

Morgado

Huster

2012

Journal of Biological Chemistry

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Background: Little tertiary structure information is available for the toxic intermediates in the amyloid-␤ (A␤) fibrillation process. Results: A␤ protofibrils show tertiary contacts between Glu-22 and Ile-31, which are not present in mature fibrils. Conclusion: A␤ protofibrils share tertiary structure features with oligomers but not with mature fibrils. Significance: A␤ protofibrils must undergo a major structural reorientation in the development of mature A␤ fibrils.We have studied tertiary contacts in protofibrils and mature fibrils of amyloid-␤ (A␤) peptides using solid-state NMR spectroscopy. Although intraresidue contacts between Glu-22 and Ile-31 were found in A␤ protofibrils, these contacts were completely absent in mature A␤ fibrils. This is consistent with the current models of mature A␤ fibrils. As these intramolecular contacts have also been reported in A␤ oligomers, our measurements suggest that A␤ protofibrils are structurally more closely related to oligomers than to mature fibrils. This suggests that some structural alterations have to take place on the pathway from A␤ oligomers/protofibrils to mature fibrils, in agreement with a model that suggests a conversion of intramolecular hydrogen-bonded structures of A␤ oligomers to the intermolecular stabilized mature fibrils (Hoyer, W., Grönwall, C., Jonsson, A., Ståhl, S., and Härd, T. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 5099 -5104).Alzheimer disease is characterized by extracellular deposition of plaques of amyloid-␤ (A␤) 2 peptides in the brain (1). These protein aggregates are composed of mature A␤ fibrils, which represent the end product of a long, complex, and not well understood fibrillation process (2, 3). The fibrillation pathway initiates with soluble unstructured monomeric A␤ peptides, which are converted into oligomers, protofibrils, and finally into mature fibrils (4 -6). Recently, interest in the transient A␤ intermediate structures has been growing rapidly because these species are considered to represent the cytotoxic intermediates in Alzheimer disease (7). In addition to the well studied structure (8 -12) and dynamics (13) of mature A␤ fibrils, a growing amount of data for oligomers (14 -19) and protofibrils (20, 21) has become available. With regard to the secondary structure elements, these studies revealed that oligomers and protofibrils already exhibit the characteristic two ␤-strand sections connected by a short loop also present in mature A␤ fibrils. However, there are several significant differences between theses species. For instance, the first ␤-strand of A␤ oligomers and protofibrils is significantly shorter than that in mature A␤ fibrils and has to elongate during the conversion from protofibrils to mature fibrils (20). In addition, many questions about the tertiary structure, the fibrillation process, and the conversion from one intermediate to another are still unanswered.Härd and co-workers have resolved the structure of A␤(1-40) oligomers stabilized by an Affibody and also proposed a model for the arrangement of t...

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“…To visualize retinal Aβ pathology in vivo, we had previously developed a noninvasive retinal amyloid imaging method for rodent ADtg models, using curcumin as a contrast agent (40,51). Curcumin is a natural and safe phytopolylphenol fluorochrome that binds to Aβ fibrils and oligomers with high affinity and specificity (62)(63)(64)(65)(66)(67)(68). This approach enabled noninvasive detection and monitoring of individual retinal Aβ deposits in live ADtg mice (40,51).…”

Section: Introductionmentioning

confidence: 99%

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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BACKGROUND. Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS.Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS.Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ 42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION.The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.

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Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid β-protein fibrils

Cited by 85 publications

References 75 publications

Curcumin Alters the Salt Bridge-containing Turn Region in Amyloid β(1–42) Aggregates

Curcumin Alters the Salt Bridge-containing Turn Region in Amyloid β(1–42) Aggregates

Solid-state NMR Reveals a Close Structural Relationship between Amyloid-β Protofibrils and Oligomers

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

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