CD measurements of β‐amyloid (1–40) and (1–42) in the condensed phase

Harada, Takunori; Kuroda, Reiko

doi:10.1002/bip.21543

Cited by 54 publications

(44 citation statements)

References 29 publications

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“…CD analysis has been widely used to monitor secondary structure changes of proteins [53], [54], [55], [56]. The CD spectrum of Aβ monomer did not exhibit any spectral feature of α-helix and β-sheet, but showed typical features of dominantly disordered structure (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

2013

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Halogenation of organic compounds plays diverse roles in biochemistry, including selective chemical modification of proteins and improved oral absorption/blood-brain barrier permeability of drug candidates. Moreover, halogenation of aromatic molecules greatly affects aromatic interaction-mediated self-assembly processes, including amyloid fibril formation. Perturbation of the aromatic interaction caused by halogenation of peptide building blocks is known to affect the morphology and other physical properties of the fibrillar structure. Consequently, in this article, we investigated the ability of halogenated ligands to modulate the self-assembly of amyloidogenic peptide/protein. As a model system, we chose amyloid-beta peptide (Aβ), which is implicated in Alzheimer’s disease, and a novel modulator of Aβ aggregation, erythrosine B (ERB). Considering that four halogen atoms are attached to the xanthene benzoate group in ERB, we hypothesized that halogenation of the xanthene benzoate plays a critical role in modulating Aβ aggregation and cytotoxicity. Therefore, we evaluated the modulating capacities of four ERB analogs containing different types and numbers of halogen atoms as well as fluorescein as a negative control. We found that fluorescein is not an effective modulator of Aβ aggregation and cytotoxicity. However, halogenation of either the xanthenes or benzoate ring of fluorescein substantially enhanced the inhibitory capacity on Aβ aggregation. Such Aβ aggregation inhibition by ERB analogs except rose bengal correlated well to the inhibition of Aβ cytotoxicity. To our knowledge, this is the first report demonstrating that halogenation of aromatic rings substantially enhance inhibitory capacities of small molecules on Aβ-associated neurotoxicity via Aβ aggregation modulation.

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Section: Resultsmentioning

confidence: 99%

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

2013

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“…For example, studies using atomic force microscopy and scanning tunneling microscopy showed that the structures of dimers, tetramers, and other low-molecular-weight (MW) A␤ oligomers were consistent with the model of the A␤ monomers as ␤-hairpins (Losic et al, 2006;Mastrangelo et al, 2006). The most recent and accurate circular dichroism (CD) measurements of A␤ 1-40/42 (Harada and Kuroda, 2011) showed that A␤ peptides themselves have a strong tendency to form ␤-sheet rich structures during the transition to condensed phases, even without the help of a special effect of hydrophobichydrophilic interface.…”

Section: Introductionmentioning

confidence: 95%

Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease

Streltsov¹,

Varghese²,

Masters³

et al. 2011

J. Neurosci.

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Alzheimer's disease is a progressive neurodegenerative disorder associated with the presence of amyloid-␤ (A␤) peptide fibrillar plaques in the brain. However, current evidence suggests that soluble nonfibrillar A␤ oligomers may be the major drivers of A␤-mediated synaptic dysfunction. Structural information on these A␤ species has been very limited because of their noncrystalline and unstable nature. Here, we describe a crystal structure of amylogenic residues 18 -41 of the A␤ peptide (equivalent to the p3 ␣/␥-secretase fragment of amyloid precursor protein) presented within the CDR3 loop region of a shark Ig new antigen receptor (IgNAR) single variable domain antibody. The predominant oligomeric species is a tightly associated A␤ dimer, with paired dimers forming a tetramer in the crystal caged within four IgNAR domains, preventing uncontrolled amyloid formation. Our structure correlates with independently observed features of small nonfibrillar A␤ oligomers and reveals conserved elements consistent with residues and motifs predicted as critical in A␤ folding and oligomerization, thus potentially providing a model system for nonfibrillar oligomer formation in Alzheimer's disease.

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“…7,[9][10][11][12][13] Despite such difficulties, there is a number of situations that demand the use of solid state rather than solution CD. [25][26][27] Second, the observation of chirogenic phenomena occurring in the solid state, which would be lost upon dissolution: these include the formation of crystals by spontaneous resolution of optically labile species, [28][29][30][31] co-crystals between a chiral species and an achiral or optically labile one, [32][33][34][35][36][37] and chiral crystals of achiral species. [25][26][27] Second, the observation of chirogenic phenomena occurring in the solid state, which would be lost upon dissolution: these include the formation of crystals by spontaneous resolution of optically labile species, [28][29][30][31] co-crystals between a chiral species and an achiral or optically labile one, [32][33][34][35][36][37] and chiral crystals of achiral species.…”

Section: Introductionmentioning

confidence: 99%

Solid‐state Circular Dichroism and Hydrogen Bonding, Part 2: The Case of Hypothemycin Re‐investigated

Pescitelli

2012

Chirality

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The impact of crystalline forces on the solid-state circular dichroism (CD) spectrum of hypothemycin (), a biologically active molecule extracted from natural sources, has been analyzed by means of time-dependent density functional theory CD calculations. Input structures were extracted from the X-ray geometry of and consisted in the isolated molecule, its cluster with five water molecules, and 20 different dimers (plus water molecules) representative of all the closest neighbors found in the crystal. The effects of solid-state intermolecular hydrogen bonds and through-space exciton couplings in determining the solid-state CD spectrum of hypothemycin were evaluated and compared.

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CD measurements of β‐amyloid (1–40) and (1–42) in the condensed phase

Cited by 54 publications

References 29 publications

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

Halogenation Generates Effective Modulators of Amyloid-Beta Aggregation and Neurotoxicity

Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease

Solid‐state Circular Dichroism and Hydrogen Bonding, Part 2: The Case of Hypothemycin Re‐investigated

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