Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Fatafta, Hebah; Khaled, Mohammed; Owen, Michael C.; Sayyed-Ahmad, Abdallah; Strodel, Birgit

doi:10.1073/pnas.2106210118

Cited by 74 publications

(120 citation statements)

References 69 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…Previously, it has been shown that electrostatic interactions between the highly charged N‐terminal domain and residues F20‐A30 with mixed membranes are the driving force for the association of the dimer to the surface of the lipid bilayers 37 . Herein, residues G25‐A30 in conformations A2, A4, and C1 to C3 interact with the DOPC bilayer.…”

Section: Resultsmentioning

confidence: 96%

See 1 more Smart Citation

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

Press-Sandler

Miller

2022

Protein Science

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 96%

“…Previously, computational studies examined the binding of Aβ dimers on membrane surfaces, 36 , 37 , 38 and as transmembrane aggregates 28 , 39 , 40 , 41 on surface of different types of membranes. Some of these studies investigated Aβ dimer fragments, such as Aβ 17–42 28 and Aβ 29–42 .…”

Section: Introductionmentioning

confidence: 99%

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

Press-Sandler

Miller

2022

Protein Science

View full text Add to dashboard Cite

show abstract

“…The importance of GM1 in the Aβ–membrane interaction has also been demonstrated for another membrane model. 42 …”

Section: Resultsmentioning

confidence: 99%

“… 40 , 41 A different neuronal membrane model was used to study the dimerization of Aβ42 near the membrane using MD simulations. 42 In this work, we also used all-atom MD simulations, as they were successful in characterizing Aβ monomers and low-weight oligomers in solution 43 − 45 and on the membrane surface. 31 , 32 We studied three systems, including pure membrane without Aβ, membrane–dodecamer complex, and membrane–fibril complex.…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…After incubation, the spectra of all variants changed drastically, featuring a minimum at ~216–227 nm and a maximum at ~196 nm ( Figure 3 B). This indicated a transition to β-sheet secondary structure [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Cited by 74 publications

References 69 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

Contact Info

Product

Resources

About