Disorder-to-order transition of the amyloid-β peptide upon lipid binding

Fatafta, Hebah; Kav, Batuhan; Bundschuh, Bastian F.; Loschwitz, Jennifer; Strodel, Birgit

doi:10.1016/j.bpc.2021.106700

Cited by 62 publications

(78 citation statements)

References 61 publications

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“…The DOPC bilayer induces the hydrophobic interactions between the monomers within the “fibril‐like” dimers and stabilizes the dimers by activating the intramolecular D23‐K38 salt‐bridge interactions. The intramolecular hydrophobic interactions were obtained also in simulations of Aβ monomer in membrane 50 . Therefore, we propose that overall, the DOPC bilayer promotes the primary nucleation of the “fibril‐like” dimers.…”

Section: Resultsmentioning

confidence: 58%

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Molecular insights into the primary nucleation of polymorphic amyloid β dimers in DOPC lipid bilayer membrane

Press-Sandler

Miller

2022

Protein Science

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Alzheimer's disease (AD) pathology is characterized by loss of memory cognitive and behavioral deterioration. One of the hallmarks of AD is amyloid β (Aβ) plaques in the brain that consists of Aβ oligomers and fibrils. It is accepted that oligomers, particularly dimers, are toxic species that are produced extracellularly and intracellularly in membranes. It is believed that the disruption of membranes by polymorphic Aβ oligomers is the key for the pathology of AD. This is a first study that investigate the effect of polymorphic “α‐helix/random coil” and “fibril‐like” Aβ dimers on 1,2‐dioleoyl‐ sn ‐glycero‐3‐phosphocholine (DOPC) membrane. It has been found that the DOPC membrane promotes Aβ 1–42 “fibril‐like” dimers and impedes Aβ 1–42 “α‐helix/random coil” dimers. The N‐termini domains within Aβ 1–42 dimers play a role in Aβ aggregation in membrane milieus. In addition, the aromatic π–π interactions (involving residues F19 and F20 in Aβ 1–42 ) are the driving forces for the hydrophobic interactions that initiate the primary nucleation of polymorphic Aβ 1–42 dimers within DOPC membrane. Finally, the DOPC bilayer membrane thickness is locally decreased, and it is disrupted by an embedded distinct Aβ 1–42 dimer, due to relatively large contacts between Aβ 1–42 monomers and the DOPC membrane. This study reveals insights into the molecular mechanisms by which polymorphic early‐stage Aβ 1–42 dimers have distinct impacts on DOPC membrane.

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Section: Resultsmentioning

confidence: 58%

“…The intramolecular hydrophobic interactions were obtained also in simulations of Aβ monomer in membrane. 50 Therefore, we propose that overall, the DOPC bilayer promotes the primary nucleation of the "fibril-like" dimers.…”

Section: Dopc Bilayer Promotes the Primary Nucleation Of The "Fibril-...mentioning

confidence: 91%

Molecular insights into the primary nucleation of polymorphic amyloid β dimers in DOPC lipid bilayer membrane

Press-Sandler

Miller

2022

Protein Science

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“… 75 The interaction with the lipid tails was shown to allow Aβ to form a stable helical structure. 76 …”

Section: Resultsmentioning

confidence: 99%

Amyloid β Dodecamer Disrupts the Neuronal Membrane More Strongly than the Mature Fibril: Understanding the Role of Oligomers in Neurotoxicity

et al. 2022

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The amyloid cascade hypothesis states that senile plaques, composed of amyloid β (Aβ) fibrils, play a key role in Alzheimer’s disease (AD). However, recent experiments have shown that Aβ oligomers are more toxic to neurons than highly ordered fibrils. The molecular mechanism underlying this observation remains largely unknown. One of the possible scenarios for neurotoxicity is that Aβ peptides create pores in the lipid membrane that allow Ca 2+ ions to enter cells, resulting in a signal of cell apoptosis. Hence, one might think that oligomers are more toxic due to their higher ability to create ion channels than fibrils. In this work, we study the effect of Aβ42 dodecamer and fibrils on a neuronal membrane, which is similar to that observed in AD patients, using all-atom molecular dynamics simulations. Due to short simulation times, we cannot observe the formation of pores, but useful insight on the early events of this process has been obtained. Namely, we showed that dodecamer distorts the lipid membrane to a greater extent than fibrils, which may indicate that ion channels can be more easily formed in the presence of oligomers. Based on this result, we anticipate that oligomers are more toxic than mature fibrils, as observed experimentally. Moreover, the Aβ–membrane interaction was found to be governed by the repulsive electrostatic interaction between Aβ and the ganglioside GM1 lipid. We calculated the bending and compressibility modulus of the membrane in the absence of Aβ and obtained good agreement with the experiment. We predict that the dodecamer will increase the compressibility modulus but has little effect on the bending modulus. Due to the weak interaction with the membrane, fibrils insignificantly change the membrane elastic properties.

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“…Most of the tested mutants showed a shorter lag time and characteristic time compared to the WT Aβ peptide. The explanation of the partly drastic alteration of the fibrillation kinetics, especially in the Gly 33 Ala mutant, lies in the modification of the folding energy landscape resulting in an acceleration of kinetically relevant steps by destabilizing specific oligomeric structures and/or the emergence of alternative pathways with different oligomers [ 3 , 4 , 41 ]. The kinetics data suggest an importance of positions Phe 20 as well as Gly 33 for fibril growth and the formation and/or stabilization of intermediate species.…”

Section: Discussionmentioning

confidence: 99%

Probing the Influence of Single-Site Mutations in the Central Cross-β Region of Amyloid β (1–40) Peptides

et al. 2021

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Amyloid β (Aβ) is a peptide known to form amyloid fibrils in the brain of patients suffering from Alzheimer’s disease. A complete mechanistic understanding how Aβ peptides form neurotoxic assemblies and how they kill neurons has not yet been achieved. Previous analysis of various Aβ40 mutants could reveal the significant importance of the hydrophobic contact between the residues Phe19 and Leu34 for cell toxicity. For some mutations at Phe19, toxicity was completely abolished. In the current study, we assessed if perturbations introduced by mutations in the direct proximity of the Phe19/Leu34 contact would have similar relevance for the fibrillation kinetics, structure, dynamics and toxicity of the Aβ assemblies. To this end, we rationally modified positions Phe20 or Gly33. A small library of Aβ40 peptides with Phe20 mutated to Lys, Tyr or the non-proteinogenic cyclohexylalanine (Cha) or Gly33 mutated to Ala was synthesized. We used electron microscopy, circular dichroism, X-ray diffraction, solid-state NMR spectroscopy, ThT fluorescence and MTT cell toxicity assays to comprehensively investigate the physicochemical properties of the Aβ fibrils formed by the modified peptides as well as toxicity to a neuronal cell line. Single mutations of either Phe20 or Gly33 led to relatively drastic alterations in the Aβ fibrillation kinetics but left the global, as well as the local structure, of the fibrils largely unchanged. Furthermore, the introduced perturbations caused a severe decrease or loss of cell toxicity compared to wildtype Aβ40. We suggest that perturbations at position Phe20 and Gly33 affect the fibrillation pathway of Aβ40 and, thereby, influence the especially toxic oligomeric species manifesting so that the region around the Phe19/Leu34 hydrophobic contact provides a promising site for the design of small molecules interfering with the Aβ fibrillation pathway.

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Disorder-to-order transition of the amyloid-β peptide upon lipid binding

Cited by 62 publications

References 61 publications

Molecular insights into the primary nucleation of polymorphic amyloid β dimers in DOPC lipid bilayer membrane

Molecular insights into the primary nucleation of polymorphic amyloid β dimers in DOPC lipid bilayer membrane

Amyloid β Dodecamer Disrupts the Neuronal Membrane More Strongly than the Mature Fibril: Understanding the Role of Oligomers in Neurotoxicity

Probing the Influence of Single-Site Mutations in the Central Cross-β Region of Amyloid β (1–40) Peptides

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