Aβ40(L17A/F19A) mutant diminishes the aggregation and neurotoxicity of Aβ40

Chen, Yi Ru; Huang, Hsien Bin; Lo, Chi Jen; Wang, Chih Ching; Su, Chia Li; Liu, Hsin Tzu; Shiao, Ming‐Shi; Lin, Ta Hsien; Chen, Yi‐Chen

doi:10.1016/j.bbrc.2010.12.133

Cited by 12 publications

(19 citation statements)

References 21 publications

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“…Both at 48 hours and 72 hours, the toxicity induced by Aβ40(E22G) was more severe than with other peptides. Similar to a previous study [37], Aβ40(L17A/F19A) showed less toxicity than other peptides. However, toxicity induced by Aβ40(L17A/F19A/E22G) was approximately the same as Aβ40, suggesting that alanine replacement of L17 and F19 reduced the cytotoxicity induced by Aβ40(E22G), which is consistent with the aggregation rate and structural stability.…”

Section: Resultssupporting

confidence: 89%

“…Previously we replaced residues L17 and F19 with alanine, resulting in an increase in structural stability and reduction of toxicity [37]. We used the same strategy [37] to test the effect of L17A and F19A on structural stability and toxicity of the most toxic FAD mutant, Arctic-type Aβ peptide [Aβ 40 (E22G)].…”

Section: Resultsmentioning

confidence: 99%

“…We used the same strategy [37] to test the effect of L17A and F19A on structural stability and toxicity of the most toxic FAD mutant, Arctic-type Aβ peptide [Aβ 40 (E22G)]. Figures 1 (B) and (D) show the CD spectra for Aβ 40 (L17A/F19A) and Aβ 40 (L17A/F19A/E22G).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we identified L17 and F19 as key amino acids in the stabilization of the Aβ 40 conformation. By constructing an Aβ 40 (L17A/F19A) mutant, we further demonstrated that replacement of L17 and F19 with alanine can stabilize the Aβ conformation, reduce Aβ aggregation, and diminish Aβ-induced neurotoxicity [37]. Most Aβ peptides of FAD contain one point mutation of wild-type Aβ [21]–[26].…”

Section: Introductionmentioning

confidence: 84%

“…To further investigate the effects of L17A/F19A mutations on Aβ properties, we used the same strategy as a previous study [37] and constructed an Aβ 40 (L17A/F19A/E22G) mutant to characterize and compare the related properties with the genetic Arctic mutation of Aβ 40 (E22G), which has been shown to be the most toxic FAD Aβ mutant [23]. We wished to determine whether the L17A/F19A mutations can result in stable conformations and less neurotoxicity not only in wild-type Aβ, but also in FAD.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Alanine Replacement of L17 and F19 on the Aggregation and Neurotoxicity of Arctic-Type Aβ40

Chen¹,

Huang

et al. 2013

PLoS ONE

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Alzheimer’s disease is the most common form of neurodegenerative disease. Beta-amyloid peptides (Aβ) are responsible for neuronal death both in vitro and in vivo. Previously, L17 and F19 residues were identified as playing key roles in the stabilization of the Aβ40 conformation and in the reduction of its neurotoxicity. In this study, the effects of L17A/F19A mutations on the neurotoxicity of Aβ genetic mutant Arctic-type Aβ40(E22G) were tested. The results showed that compared to Aβ40(E22G), Aβ40(L17A/F19A/E22G) reduced the rate of conformation conversion, aggregation, and cytotoxicity, suggesting that L17 and F19 are critical residues responsible for conformational changes which may trigger the neurotoxic cascade of Aβ. Aβ40(L17A/F19A/E22G) also had decreased damage due to reactive oxygen species. The results are consistent with the discordant helix hypothesis, and confirm that residues 17–25 are in the discordant helix region. Compared to Aβ40(L17A/F19A), reduction in aggregation of Aβ40(L17A/F19A/E22G) was less significantly decreased. This observation provides an explanation based on the discordant helix hypothesis that the mutation of E22 to G22 of Aβ40(E22G) alters the propensity of the discordant helix. Arctic-type Aβ40(E22G) aggregates more severely than wild-type Aβ40, with a consequential increase in toxicity.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Effect of Alanine Replacement of L17 and F19 on the Aggregation and Neurotoxicity of Arctic-Type Aβ40

Chen¹,

Huang

et al. 2013

PLoS ONE

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Molecular insights into the effect L17A/F19A double mutation on the structure and dynamics of Aβ₄₀: A molecular dynamics simulation study

Saini

Shuaib

Goyal

2018

J of Cellular Biochemistry

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The aggregation of amyloid-β (Aβ) peptide has been associated with the pathogenesis of Alzheimer disease. The recent studies highlighted that L17A/F19A double mutation increases the structural stability of Aβ and diminish Aβ aggregation. However, the underlying effect of L17A/F19A double mutation on the Aβ structure and dynamics remain elusive. In this regard, the influence of L17A/F19A double mutation on the structure and dynamics of Aβ was investigated using all-atom molecular dynamics (MD) simulation. MD simulation reveals that mechanism behind modulation of Aβ aggregation is associated with a decrease in the β-sheet content and dynamics of the salt bridge D23-K28. The secondary structure analysis highlight more abundant α-helix content in the central hydrophobic core and C-terminal region of Aβ upon L17A/F19A double mutation that is consistent with circular dichroism (CD) results. The free-energy landscape reveal that coil conformation is the most dominant conformation in Aβ whereas the helical conformation is the most-populated and energetically favorable conformation in Aβ (L17A/F19A). MD simulation, in accord with the experiment, highlight that L17A/F19A double mutation diminish Aβ aggregation as the population of the fibril-prone state substantially decreased. The present study, in conjunction with experiment, highlight that L17 and F19 are the critical residues involved in the conformational change that triggers a neurotoxic cascade of Aβ . Overall, MD simulation provides key structural and physical insights into the reduced Aβ aggregation upon L17A/F19A double mutation and an atomic picture of the L17A/F19A-mediated conformational changes in Aβ .

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How Single Site Mutations Can Help Understanding Structure Formation of Amyloid β₁₋₄₀

Schwarze

Huster

2023

Macromolecular Bioscience

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Amyloid fibrils represent the structural endpoint on the energetic (mis)folding landscape of very many proteins. Physiologically, amyloid fibrils are observed as a characteristic hallmark in misfolding diseases often associated with degenerative and neurodegenerative disorders. In the beginning of the scientific discussion, the focus is laid on the fibrillar state, but over the time it becomes increasingly clear that low molecular weight and transient aggregates are of crucial importance for pathological mechanisms. Structural studies find different intra‐ and intermolecular contacts for the most well‐studied peptide amyloid β (Aβ) depending on the stage of fibrillation. In particular, the contact between residues phenylalanine 19 (F19) and leucine 34 (L34) seems to be highly conserved, suggesting that it must be of particular significance for Aβ misfolding and possibly the pathological properties of the peptide. This review aims to highlight the rational and the usefulness of point mutations in Aβ peptides and their impact on the critical interstrand contact F19−L34 depending on the stage of fibrillation. While the amyloid structure of Aβ is very robust against quite a few modifications, the toxicity of mutated Aβ molecules highly depends on the F19−L34 contact.

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Aβ40(L17A/F19A) mutant diminishes the aggregation and neurotoxicity of Aβ40

Cited by 12 publications

References 21 publications

Effect of Alanine Replacement of L17 and F19 on the Aggregation and Neurotoxicity of Arctic-Type Aβ40

Effect of Alanine Replacement of L17 and F19 on the Aggregation and Neurotoxicity of Arctic-Type Aβ40

Molecular insights into the effect L17A/F19A double mutation on the structure and dynamics of Aβ₄₀: A molecular dynamics simulation study

How Single Site Mutations Can Help Understanding Structure Formation of Amyloid β₁₋₄₀

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Aβ40(L17A/F19A) mutant diminishes the aggregation and neurotoxicity of Aβ40

Cited by 12 publications

References 21 publications

Effect of Alanine Replacement of L17 and F19 on the Aggregation and Neurotoxicity of Arctic-Type Aβ40

Effect of Alanine Replacement of L17 and F19 on the Aggregation and Neurotoxicity of Arctic-Type Aβ40

Molecular insights into the effect L17A/F19A double mutation on the structure and dynamics of Aβ40: A molecular dynamics simulation study

How Single Site Mutations Can Help Understanding Structure Formation of Amyloid β1−40

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Product

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Molecular insights into the effect L17A/F19A double mutation on the structure and dynamics of Aβ₄₀: A molecular dynamics simulation study

How Single Site Mutations Can Help Understanding Structure Formation of Amyloid β₁₋₄₀