Coarse-grained MD simulations reveal beta-amyloid fibrils of various sizes bind to interfacial liquid-ordered and liquid-disordered regions in phase separated lipid rafts with diverse membrane-bound conformational states

Cheng, Sara Y.; Cao, Yiyi; Rouzbehani, Marzieh; Cheng, Kwan Hon

doi:10.1016/j.bpc.2020.106355

Cited by 30 publications

(29 citation statements)

References 55 publications

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“…This might further lead to interruptions of the C-terminal hydrogen-bonding network and more insertion of lipid molecules into the β-sheets. The Aβ 40 oligomer core eventually formed localized β-sheets with a smaller number of assembled β-strands, similar to the scenarios described in previous computational simulations. − This model explained the 13 C-PITHIRDs results at V36: Although the bulk C-terminal β-sheets network broke, there was no change in the 13 C signal decay, because the PITHIRDs decay curves were determined by the shortest 13 C– 13 C interstrand distances (i.e., the strongest dipolar coupling). In addition, the 13 C-detected REDOR dephasing at V36 only reached ∼25% (instead of 100% for an ideal 13 C– 31 P two-spin model), because a large population of 13 Cs were shielded from the lipid phosphate groups by the localized β-sheets.…”

supporting

confidence: 76%

Time-Dependent Lipid Dynamics, Organization and Peptide-Lipid Interaction in Phospholipid Bilayers with Incorporated β-Amyloid Oligomers

Wang

Doherty

Klees

et al. 2020

J. Phys. Chem. Lett.

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Nonfibrillar β-amyloid (Aβ) oligomers are considered as major neurotoxic species in the pathology of Alzheimer's disease. The presence of Aβ oligomers was shown to cause membrane disruptions in a broad range of model systems. However, the molecular basis of such a disruption process remains unknown. We previously demonstrated that membrane-incorporated 40-residue Aβ (Aβ 40 ) oligomers could form coaggregates with phospholipids. This process occurred more rapidly than the fibrillization of Aβ 40 and led to more severe membrane disruption. The present study probes the time-dependent changes in lipid dynamics, bilayer structures, and peptide-lipid interactions along the time course of the oligomer-induced membrane disruption, using solid-state NMR spectroscopy. Our results suggest the presence of certain intermediate states with phospholipid molecules entering the C-terminal hydrogen-bonding networks of the Aβ 40 oligomeric cores. This work provides insights on the molecular mechanisms of Aβ 40 -oligomer-induced membrane disruption.

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supporting

confidence: 76%

Time-Dependent Lipid Dynamics, Organization and Peptide-Lipid Interaction in Phospholipid Bilayers with Incorporated β-Amyloid Oligomers

Wang

Doherty

Klees

et al. 2020

J. Phys. Chem. Lett.

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“…Molecular analysis of the interaction between Aβ oligomers and the cell membrane is of great importance to reveal the biological features of Aβ oligomer neurotoxicity. Previous reports demonstrated that the interaction of Aβ oligomers and ganglioside‐containing cell membranes developed structural conversions from α‐helices to β‐sheets in Aβ aggregates (Cheng et al, 2020; Rudajev et al, 2020). However, the precise pathomechanisms of neuronal damage caused by Aβ oligomers remain uncertain because of their transient and heterogeneous properties (Cawood et al, 2021; Nguyen et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of seeding activity of amyloid β‐protein aggregates in vitro

Nakano

Hamaguchi

Ikeda

et al. 2022

Journal of Neurochemistry

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“…Cellular membranes appear to play an important role in promoting formation of Aβ oligomers . Aβ fibrils can bind to monosialotetrahexosylganglioside (GM1) in rafts with various membrane-bound conformations that cause membrane disruption. − Metal ions like copper and zinc are also involved in the aggregation process of Aβ . Although Aβ42 is more neurotoxic than Aβ40 as a single alloform, the interplay between these Aβ species might also be important in AD pathology .…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Conformation-Restricted Amyloid β Peptide and Immunoreactivity of Its Antibody in Human AD brain

Kageyama

Irie

Matsushima

et al. 2021

ACS Chem. Neurosci.

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Characterization of amyloid β (Aβ) oligomers, the transition species present prior to the formation of Aβ fibrils and that have cytotoxicity, has become one of the major topics in the investigations of Alzheimer’s disease (AD) pathogenesis. However, studying pathophysiological properties of Aβ oligomers is challenging due to the instability of these protein complexes in vitro. Here, we report that conformation-restricted Aβ42 with an intramolecular disulfide bond at positions 17 and 28 (SS-Aβ42) formed stable Aβ oligomers in vitro. Thioflavin T binding assays, nondenaturing gel electrophoresis, and morphological analyses revealed that SS-Aβ42 maintained oligomeric structure, whereas wild-type Aβ42 and the highly aggregative Aβ42 mutant with E22P substitution (E22P-Aβ42) formed Aβ fibrils. In agreement with these observations, SS-Aβ42 was more cytotoxic compared to the wild-type and E22P-Aβ42 in cell cultures. Furthermore, we developed a monoclonal antibody, designated TxCo-1, using the toxic conformation of SS-Aβ42 as immunogen. X-ray crystallography of the TxCo-1/SS-Aβ42 complex, enzyme immunoassay, and immunohistochemical studies confirmed the recognition site and specificity of TxCo-1 to SS-Aβ42. Immunohistochemistry with TxCo-1 antibody identified structures resembling senile plaques and vascular Aβ in brain samples of AD subjects. However, TxCo-1 immunoreactivity did not colocalize extensively with Aβ plaques identified with conventional Aβ antibodies. Together, these findings indicate that Aβ with a turn at positions 22 and 23, which is prone to form Aβ oligomers, could show strong cytotoxicity and accumulated in brains of AD subjects. The SS-Aβ42 and TxCo-1 antibody should facilitate understanding of the pathological role of Aβ with toxic conformation in AD.

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Coarse-grained MD simulations reveal beta-amyloid fibrils of various sizes bind to interfacial liquid-ordered and liquid-disordered regions in phase separated lipid rafts with diverse membrane-bound conformational states

Cited by 30 publications

References 55 publications

Time-Dependent Lipid Dynamics, Organization and Peptide-Lipid Interaction in Phospholipid Bilayers with Incorporated β-Amyloid Oligomers

Time-Dependent Lipid Dynamics, Organization and Peptide-Lipid Interaction in Phospholipid Bilayers with Incorporated β-Amyloid Oligomers

Inactivation of seeding activity of amyloid β‐protein aggregates in vitro

Characterization of a Conformation-Restricted Amyloid β Peptide and Immunoreactivity of Its Antibody in Human AD brain

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