Site-specific dynamics of amyloid formation and fibrillar configuration of Aβ<sub>1–23</sub> using an unnatural amino acid

Liu, Haiyang; Lantz, Richard; Cosme, Patrick; Rivera, Nelson; Andino, Carlos; González, Walter; Terentis, Andrew C.; Wojcikiewicz, Ewa P.; Oyola, Rolando; Mikšovská, Jaroslava; Du, Deguo

doi:10.1039/c5cc00149h

Cited by 23 publications

(28 citation statements)

References 43 publications

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“…As depicted in Figure and Figure , the four mutants all show a significant decrease in Phe CN fluorescence intensity over the period of aggregation. It is worth noting that the fluorescence intensity of the free Phe CN amino acid, or the Phe CN residue in an Aβ fragment peptide mutant that does not aggregate to form amyloids, remains stable over time (Figure S2). This suggests that the observed Phe CN fluorescence intensity changes of the Aβ40 mutants are not caused by the spectroscopic instability of the Phe CN fluorophore, but rather by aggregation‐induced local environmental changes.…”

Section: Figuresupporting

confidence: 89%

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

et al. 2018

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Elucidating local dynamics of protein aggregation is crucial for understanding the mechanistic details of protein amyloidogenesis. Herein, we studied the residue‐specific dynamics and local environmental changes of Aβ40 along the course of aggregation by using para‐cyanophenylalanine (PheCN) as a fluorescent and vibrational probe. Our results show that the PheCN residues introduced at various positions all exhibited an immediate decay of fluorescence intensity, indicating a relatively synergistic process in early oligomer formation. The fast decreases in the fluorescence intensities of residues 19 and 20 in the central hydrophobic core region and residue 10 in the N‐terminal region suggest that they play crucial roles in the formation of the oligomeric core. The PheCN4 residue exhibits a remarkably slower decrease in fluorescence intensity, implicating its dynamic conformational characteristics in oligomer and fibril formation. Our results also suggest that the N‐terminal residues in fibrils are surrounded by a relatively hydrophobic local environment, as opposed to being solvated.

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Section: Figuresupporting

confidence: 89%

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

et al. 2018

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“…41 In brief, the monomerized Aβ40 peptide solution was diluted to a final concentration of 12 μM in pH 7.4 phosphate buffer (50 mM Na phosphate, 150 mM NaCl) containing 20 μM ThT. 100 μL solution was transferred into wells of a 96-well microplate (Costar black, clear bottom).…”

Section: Experimental Methodsmentioning

confidence: 99%

Effects of Charged Cholesterol Derivatives on Aβ40 Amyloid Formation

et al. 2015

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Understanding of the mechanistic progess of Amyloid-β peptide (Aβ) aggregation is critical for elucidating the underlying pathogenesis of Alzheimer’s disease (AD). Herein, we report for the first time the effects of two cholesterol derivatives, negatively charged cholesterol sulfate (cholesterol-SO4) and positively charged 3β-[N-(dimethylaminoethane)carbamoyl]-cholesterol (DC-cholesterol), on the fibrillization of Aβ40. Our results demonstrate that both of the nonvesicle forms of cholesterol-SO4 and DC-cholesterol moderately accelerate the aggregation rate of Aβ40. This effect is similar to that observed for unmodified cholesterol, indicating the importance of hydrophobic interactions in binding of Aβ40 to these steroid molecules. Furthermore, we show that the vesicles formed at higher concentrations of anionic cholesterol-SO4 facilitate Aβ40 aggregation rate markedly. In contrast, the cationic DC-cholesterol vesicles show the ability to inhibit Aβ40 fibril formation under appropriate experimental conditions. The results suggest that the electrostatic interactions between Aβ40 and the charged vesicles can be of great importance in regulating Aβ40-vesicle interaction. Our results also indicate that the structural properties of the aggregates of the cholesterol derivatives, including the surface charge and the size of the vesicles, are critical in regulating the effects of these vesicles on Aβ40 aggregation kinetics.

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“…[4c,e, 6] Recently, this probe has also been used to monitor the formation of amyloid fibrils. [7] Here, we replaced the Tyr10, Phe19, Phe20, and Phe4 residues in Aβ40 with Phe CN , respectively (Figure 1A), to explore local dynamics and environmental changes of specific residues along the pathway of Aβ oligomerization and fibrillization.…”

mentioning

confidence: 99%

“…[4] As depicted in Figure 2 and Figure 3, the four mutants all show a significant decrease in Phe CN fluorescence intensity over the period of aggregation. It is worth noting that the fluorescence intensity of the free Phe CN amino acid, or the Phe CN residue in an Aβ fragment peptide mutant that does not aggregate to form amyloids, [7c] remains stable over time (Figure S2). This suggests that the observed Phe CN fluorescence intensity changes of the Aβ40 mutants are not caused by the spectroscopic instability of the Phe CN fluorophore, but rather by aggregation-induced local environmental changes.…”

mentioning

confidence: 99%

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

et al. 2018

Self Cite

View full text Add to dashboard Cite

Elucidating local dynamics of protein aggregation is crucial for understanding the mechanistic details of protein amyloidogenesis. Herein, we studied the residue-specific dynamics and local environmental changes of Ab40 along the course of aggregation by using para-cyanophenylalanine (PheCN) as a fluorescent and vibrational probe. Our results show that the PheCN residues introduced at various positions all exhibited an immediate decay of fluorescence intensity, indicating a relatively synergistic process in early oligomer formation. The fast decreases in the fluorescence intensities of residues 19 and 20 in the central hydrophobic core region and residue 10 in the N-terminal region suggest that they play crucial roles in the formation of the oligomeric core. The PheCN4 residue exhibits a remarkably slower decrease in fluorescence intensity, implicating its dynamic conformational characteristics in oligomer and fibril formation. Our results also suggest that the N-terminal residues in fibrils are surrounded by a relatively hydrophobic local environment, as opposed to being solvated.

show abstract

Site-specific dynamics of amyloid formation and fibrillar configuration of Aβ_1–23 using an unnatural amino acid

Cited by 23 publications

References 43 publications

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

Effects of Charged Cholesterol Derivatives on Aβ40 Amyloid Formation

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

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Site-specific dynamics of amyloid formation and fibrillar configuration of Aβ1–23 using an unnatural amino acid

Cited by 23 publications

References 43 publications

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

Effects of Charged Cholesterol Derivatives on Aβ40 Amyloid Formation

Residue‐Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

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Site-specific dynamics of amyloid formation and fibrillar configuration of Aβ_1–23 using an unnatural amino acid