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

Aggregation of 42-residue amyloid β-protein (Aβ42) plays a pivotal role in the etiology of Alzheimer's disease (AD). Curcumin, the yellow pigment in the rhizome of turmeric, attracts considerable attention as a food component potentially preventing the pathogenesis of AD. This is because curcumin not only inhibits the aggregation of Aβ42 but also binds to its aggregates (fibrils), resulting in disaggregation. However, the mechanism of interaction between curcumin and the Aβ42 fibrils remains unclear. In this study, we analyzed the binding mode of curcumin to the Aβ42 fibrils by solid-state NMR using dipolar-assisted rotational resonance (DARR). To improve the quality of 2D spectra, 2D DARR data were processed with the covariance NMR method, which enabled us to detect weak cross peaks between carbons of curcumin and those of the Aβ42 fibrils. The observed (13)C-(13)C cross peaks indicated that curcumin interacts with the 12th and 17-21st residues included in the β-sheet structure in the Aβ42 fibrils. Interestingly, aromatic carbons adjacent to the methoxy and/or hydroxy groups of curcumin showed clear cross peaks with the Aβ42 fibrils. This suggested that these functional groups of curcumin play an important role in its interaction with the Aβ42 fibrils.

[1]  R. Brüschweiler,et al.  Covariance nuclear magnetic resonance spectroscopy. , 2004, The Journal of chemical physics.

[2]  R. Tycko,et al.  Molecular structure of amyloid fibrils: insights from solid-state NMR , 2006, Quarterly Reviews of Biophysics.

[3]  G. Lithgow,et al.  Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan , 2011, Nature.

[4]  M. Nagao,et al.  Analysis of the Secondary Structure of β-Amyloid (Aβ42) Fibrils by Systematic Proline Replacement* , 2004, Journal of Biological Chemistry.

[5]  R. Leapman,et al.  Supramolecular structural constraints on Alzheimer's beta-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. , 2002, Biochemistry.

[6]  R. Tycko.  Insights into the amyloid folding problem from solid-state NMR. , 2003, Biochemistry.

[7]  T. Shirasawa,et al.  Verification of the turn at positions 22 and 23 of the beta-amyloid fibrils with Italian mutation using solid-state NMR. , 2005, Bioorganic & medicinal chemistry.

[8]  K. Grzeschik,et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor , 1987, Nature.

[9]  S. Ganapathy,et al.  High resolution solid state 13C NMR spectra of carbons bonded to nitrogen in a sample spinning at the magic angle , 1981 .

[10]  Ehud Gazit,et al.  A possible role for π‐stacking in the self‐assembly of amyloid fibrils , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  Kenjiro Ono,et al.  Curcumin has potent anti‐amyloidogenic effects for Alzheimer's β‐amyloid fibrils in vitro , 2004, Journal of neuroscience research.

[12]  L. A. Carpino.  1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive , 1993 .

[13]  J. J. Balbach,et al.  Supramolecular Structure in Full-Length Alzheimer's β-Amyloid Fibrils: Evidence for a Parallel β-Sheet Organization from Solid-State Nuclear Magnetic Resonance , 2002 .

[14]  B. Yankner,et al.  Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Kirschner,et al.  Structural analysis of Alzheimer's beta(1-40) amyloid: protofilament assembly of tubular fibrils. , 1998, Biophysical journal.

[16]  L. Serpell,et al.  Alzheimer's amyloid fibrils: structure and assembly. , 2000, Biochimica et biophysica acta.

[17]  G. Glenner,et al.  Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein , 1984 .

[18]  P. Lansbury,et al.  The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. , 1993, Biochemistry.

[19]  G. Bodenhausen,et al.  Improving the quality of 2D solid-state NMR spectra of microcrystalline proteins by covariance analysis. , 2010, Chemical communications.

[20]  G. Fields,et al.  Solid phase peptide synthesis of 15N-gramicidins A, B, and C and high performance liquid chromatographic purification. , 2009, International journal of peptide and protein research.

[21]  William C. Nolan,et al.  Curcumin inhibits aggregation of α-synuclein , 2008, Acta Neuropathologica.

[22]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[23]  Lei Huang,et al.  Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation. , 2009, Neurotoxicology.

[24]  C. Masters,et al.  Amyloid plaque core protein in Alzheimer disease and Down syndrome. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[25]  T. Shirasawa,et al.  Verification of the Intermolecular Parallel β-Sheet in E22K-Aβ42 Aggregates by Solid-State NMR Using Rotational Resonance: Implications for the Supramolecular Arrangement of the Toxic Conformer of Aβ42 , 2008 .

[26]  U. Kikkawa,et al.  Molecular Basis for Protein Kinase C Isozyme-Selective Binding: The Synthesis, Folding, and Phorbol Ester Binding of the Cysteine-Rich Domains of All Protein Kinase C Isozymes , 1998 .

[27]  Rafael Brüschweiler,et al.  Theory of covariance nuclear magnetic resonance spectroscopy. , 2004, The Journal of chemical physics.

[28]  G. Cole,et al.  The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse , 2001, The Journal of Neuroscience.

[29]  R. Riek,et al.  3D structure of Alzheimer's amyloid-β(1–42) fibrils , 2005 .

[30]  S. Opella,et al.  Influence of nitrogen-14 on carbon-13 NMR spectra of solids , 1981 .

[31]  C. Masters,et al.  Mechanisms of Aβ mediated neurodegeneration in Alzheimer's disease , 2008 .

[32]  T. Shirasawa,et al.  Verification of the C-terminal intramolecular beta-sheet in Abeta42 aggregates using solid-state NMR: implications for potent neurotoxicity through the formation of radicals. , 2008, Bioorganic & medicinal chemistry letters.

[33]  Steven O. Smith,et al.  Ramped-Amplitude Cross Polarization in Magic-Angle-Spinning NMR , 1994 .

[34]  V. Gaponenko,et al.  Diluting abundant spins by isotope edited radio frequency field assisted diffusion. , 2004, Journal of the American Chemical Society.

[35]  Fusheng Yang,et al.  Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo* , 2005, Journal of Biological Chemistry.

[36]  J. Gestwicki,et al.  Structure–activity Relationships of Amyloid Beta‐aggregation Inhibitors Based on Curcumin: Influence of Linker Length and Flexibility , 2007, Chemical biology & drug design.

[37]  D. Teplow,et al.  Grape-Derived Polyphenolics Prevent Aβ Oligomerization and Attenuate Cognitive Deterioration in a Mouse Model of Alzheimer's Disease , 2008, The Journal of Neuroscience.

[38]  Xudong Huang,et al.  Novel drug targets based on metallobiology of Alzheimer's disease , 2010, Expert opinion on therapeutic targets.

[39]  Claudio Soto,et al.  β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer's therapy , 1998, Nature Medicine.

[40]  Richard D. Leapman,et al.  Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils , 2008, Proceedings of the National Academy of Sciences.

[41]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[42]  Takashi Morihara,et al.  Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer's Disease , 2008, Journal of Pharmacology and Experimental Therapeutics.

[43]  R. Wetzel,et al.  Hydrogen-deuterium (H/D) exchange mapping of Abeta 1-40 amyloid fibril secondary structure using nuclear magnetic resonance spectroscopy. , 2005, Biochemistry.

[44]  K. Ono,et al.  REVIEW: Curcumin and Alzheimer's Disease , 2010, CNS neuroscience & therapeutics.

[45]  Roberto Cappai,et al.  The redox chemistry of the Alzheimer's disease amyloid β peptide , 2007 .

[46]  D. Wishart,et al.  The 13C Chemical-Shift Index: A simple method for the identification of protein secondary structure using 13C chemical-shift data , 1994, Journal of biomolecular NMR.

[47]  Iva Hafner-Bratkovič,et al.  Curcumin binds to the α‐helical intermediate and to the amyloid form of prion protein – a new mechanism for the inhibition of PrPSc accumulation , 2008 .

[48]  Tak W. Kee,et al.  The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compounds , 2009, The FEBS journal.

[49]  W. Klein,et al.  Salvianolic acid B inhibits Aβ fibril formation and disaggregates preformed fibrils and protects against Aβ-induced cytotoxicty , 2008, Neurochemistry International.

[50]  Ehud Gazit,et al.  Inhibition of Amyloid Fibril Formation by Polyphenols: Structural Similarity and Aromatic Interactions as a Common Inhibition Mechanism , 2006, Chemical biology & drug design.

[51]  G. Bodenhausen,et al.  Sensitive 13C–13C correlation spectra of amyloid fibrils at very high spinning frequencies and magnetic fields , 2011, Journal of biomolecular NMR.

[52]  Kumiko Sakai-Kato,et al.  Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid β protein , 2008, Neuroscience Letters.

[53]  Gopal Thinakaran,et al.  Amyloidogenic processing of β-amyloid precursor protein in intracellular compartments , 2006, Neurology.

[54]  Kiyonori Takegoshi,et al.  13C–1H dipolar-assisted rotational resonance in magic-angle spinning NMR , 2001 .

[55]  M J Ball,et al.  beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[56]  C. Cotman,et al.  Amyloid β‐Protein Induces Its Own Production in Cultured Degenerating Cerebrovascular Smooth Muscle Cells , 1995 .

[57]  Y. Ishii,et al.  Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid , 2007, Nature Structural &Molecular Biology.

[58]  A. Olofsson,et al.  The Solvent Protection of Alzheimer Amyloid-β-(1–42) Fibrils as Determined by Solution NMR Spectroscopy* , 2006, Journal of Biological Chemistry.

[59]  T. Iwatsubo,et al.  Small Molecule Inhibitors of α-Synuclein Filament Assembly† , 2006 .

[60]  Rafael Brüschweiler,et al.  Covariance NMR spectroscopy by singular value decomposition. , 2004, Journal of magnetic resonance.

[61]  S. Constantinescu,et al.  Inhibitors of amyloid toxicity based on beta-sheet packing of Abeta40 and Abeta42. , 2006, Biochemistry.

[62]  S. DeKosky,et al.  Apolipoprotein E polymorphism and Alzheimer disease: The Indo-US Cross-National Dementia Study. , 2000, Archives of neurology.

[63]  Judianne Davis,et al.  Structural conversion of neurotoxic amyloid-β(1–42) oligomers to fibrils , 2010, Nature Structural &Molecular Biology.

[64]  J. Wade,et al.  The Role of Aβ Peptides in Alzheimers Disease , 2005 .

[65]  M. Nagao,et al.  Synthesis, aggregation, neurotoxicity, and secondary structure of various A beta 1-42 mutants of familial Alzheimer's disease at positions 21-23. , 2002, Biochemical and biophysical research communications.

[66]  A. Olofsson,et al.  Amide solvent protection analysis demonstrates that amyloid-β(1–40) and amyloid-β(1–42) form different fibrillar structures under identical conditions , 2007 .

[67]  Kiyonori Takegoshi,et al.  13C–1H dipolar-driven 13C–13C recoupling without 13C rf irradiation in nuclear magnetic resonance of rotating solids , 2003 .

[68]  B. Hyman,et al.  Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model , 2007, Journal of neurochemistry.

[69]  H. J. J. Pabon,et al.  A synthesis of curcumin and related compounds , 1964 .

[70]  M. Deschamps,et al.  Solid-state NMR covariance of homonuclear correlation spectra. , 2008, The Journal of chemical physics.

[71]  T. Shirasawa,et al.  Identification of Physiological and Toxic Conformations in Aβ42 Aggregates , 2009, Chembiochem : a European journal of chemical biology.

[72]  Ying Xu,et al.  Mapping abeta amyloid fibril secondary structure using scanning proline mutagenesis. , 2004, Journal of molecular biology.