Probing and Trapping a Sensitive Conformation: Amyloid-β Fibrils, Oligomers, and Dimers

Fawver, Janelle N.; Duong, Karen T.; Wise-Scira, Olivia; Chapa, Rachel Petrofes; Schall, Hayley E.; Coskuner, Orkid; Zhu, Xiongwei; Colom, Luis V.; Murray, Ian V.J.

doi:10.3233/jad-2012-120880

Cited by 23 publications

(22 citation statements)

References 108 publications

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“…It has been reported that different antibodies have different specificity towards Aβ species. Murray et al reported that antibody 2H4 showed better recognizing capability for Aβ fibrils than for other soluble Aβs 54,55 . As expected, the intensity was signifcantly lower from the dot with CRANAD-17 presence when antibody 2H4 was used (SI Fig.10).…”

Section: Resultsmentioning

confidence: 99%

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Design and Synthesis of Curcumin Analogues for in Vivo Fluorescence Imaging and Inhibiting Copper-Induced Cross-Linking of Amyloid Beta Species in Alzheimer’s Disease

et al. 2013

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In this article, we first designed and synthesized curcumin-based near infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species, and then an inhibitor that could attenuate crosslinking of Aβ induced by copper. According to our previous results and the possible structural stereo-hindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13–20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild type mice as young as 4-months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. In this report, according to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the crosslinking of Aβ42 induced by copper. It is well known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent crosslinking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.

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Section: Resultsmentioning

confidence: 99%

“…SeeBlue®plus2 (Invitrogen)(4-250KD) was used as a molecular weight marker. For dot blot, the reported procedure was followed 55 . The samples were dropped to a nitrocellulose membrane and dried at room temperature for 1 hour, then a western blot was performed.…”

Section: Synthesis Of Cranad-2 -6 -17 -23 -54 and -58mentioning

confidence: 99%

Design and Synthesis of Curcumin Analogues for in Vivo Fluorescence Imaging and Inhibiting Copper-Induced Cross-Linking of Amyloid Beta Species in Alzheimer’s Disease

et al. 2013

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“…The convergence of both simulations was confirmed to occur after 20 ns of simulation per replica by the cumulative secondary structure abundance (see the Supporting Information), as shown in our previous studies. 37,39,40,49 All structural and thermodynamic properties of the wild-type and E46K mutant-type αS were determined from the structures obtained from the 20 ns of simulation after convergence was reached for the replica closest to physiological temperature (310 K). The secondary structure components of both αS proteins were determined using the DSSP program, which includes hydrogen bond and dihedral angle criteria.…”

Section: ■ Methodsmentioning

confidence: 99%

Structures of the E46K Mutant-Type α-Synuclein Protein and Impact of E46K Mutation on the Structures of the Wild-Type α-Synuclein Protein

Wise-Scira

Dunn

Aloglu

et al. 2013

ACS Chem. Neurosci.

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The E46K genetic missense mutation of the wild-type α-synuclein protein was recently identified in a family of Spanish origin with hereditary Parkinson's disease. Detailed understanding of the structures of the monomeric E46K mutant-type α-synuclein protein as well as the impact of the E46K missense mutation on the conformations and free energy landscapes of the wild-type α-synuclein are required for gaining insights into the pathogenic mechanism of Parkinson's disease. In this study, we use extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to assess the secondary and tertiary structural properties as well as the conformational preferences of the monomeric wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment. We also present the residual secondary structure component conversion stabilities with dynamics using a theoretical strategy, which we most recently developed. To the best of our knowledge, this study presents the first detailed comparison of the structural and thermodynamic properties of the wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment at the atomic level with dynamics. We find that the E46K mutation results not only in local but also in long-range changes in the structural properties of the wild-type α-synuclein protein. The mutation site shows a significant decrease in helical content as well as a large increase in β-sheet structure formation upon E46K mutation. In addition, the β-sheet content of the C-terminal region increases significantly in the E46K mutant-type αS in comparison to the wild-type αS. Our theoretical strategy developed to assess the thermodynamic preference of secondary structure transitions indicates that this shift in secondary structure is the result of a decrease in the thermodynamic preference of turn to helix conversions while the coil to β-sheet preference increases for these residues. Long-range intramolecular protein interactions of the C-terminal with the N-terminal and NAC regions increase upon E46K mutation, resulting in more compact structures for the E46K mutant-type rather than wild-type αS. However, the E46K mutant-type αS structures are less stable than the wild-type αS. Overall, our results show that the E46K mutant-type αS has a higher propensity to aggregate than the wild-type αS and that the N-terminal and C-terminal regions are reactive toward fibrillization and aggregation upon E46K mutation and we explain the associated reasons based on the structural properties herein. Small molecules or drugs that can block the specific residues forming abundant β-sheet structure, which we report here, might help to reduce the reactivity of these intrinsically disordered fibrillogenic proteins toward aggregation and their toxicity.

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“…It has been reported that different morphology of fibrillar Aβs could have different toxicity, and more twisted Aβs fibrils may have higher toxicity [13] . To further validate the effectiveness of 12-crown-4 ether, we used a dot blot for measuring the amount of profibrils/fibrils in solution with Aβ antibody 2H4, which is more specific for fibrillar/profibrillar Aβs than for monomers/oligomers [14] . Compared to the signal from the control group, a significantly lower signal (62%) was observed for the 12-crown-4 ether group after 48 hours of incubation (Fig.…”

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confidence: 99%

Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease

Tian

Zhang

et al. 2014

Chem. Commun.

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The stagnant state of drug development for Alzheimer’s disease demands new approaches for seeking promising candidates. In this report, we reasoned that non-covalent modification of amyloid beta (Aβ) peptide by crown ethers could inhibit its aggregation. To specifically target Aβs, a conjugate of Pittsburgh compound B (PiB) and 12-crown-4 ether (termed PiB-C) was synthesized. Our results indicated that the conjugate could significantly reduce the aggregation of Aβs in vitro. In addition, by two-photon microscopic imaging, we found that PiB-C could readily penetrate the BBB and efficiently label Aβ plaques and CAAs (cerebral amyloid angiophathy) in an APP-PS1 transgenic mouse.

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Probing and Trapping a Sensitive Conformation: Amyloid-β Fibrils, Oligomers, and Dimers

Cited by 23 publications

References 108 publications

Design and Synthesis of Curcumin Analogues for in Vivo Fluorescence Imaging and Inhibiting Copper-Induced Cross-Linking of Amyloid Beta Species in Alzheimer’s Disease

Design and Synthesis of Curcumin Analogues for in Vivo Fluorescence Imaging and Inhibiting Copper-Induced Cross-Linking of Amyloid Beta Species in Alzheimer’s Disease

Structures of the E46K Mutant-Type α-Synuclein Protein and Impact of E46K Mutation on the Structures of the Wild-Type α-Synuclein Protein

Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease

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