Article

Two-Step Mechanism of Membrane Disruption by Aβ through Membrane Fragmentation and Pore Formation

Department of Chemistry, University of Michigan, Ann Arbor, Michigan.
Biophysical Journal (Impact Factor: 3.97). 08/2012; 103(4):702-10. DOI: 10.1016/j.bpj.2012.06.045
Source: PubMed

ABSTRACT

Disruption of cell membranes by Aβ is believed to be one of the key components of Aβ toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by Aβ occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addition of freshly dissolved Aβ(1-40), defects form on the membrane that share many of the properties of Aβ channels originally reported from single-channel electrical recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we observed that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved Aβ(1-40) is weakly observed in the absence of gangliosides, fiber-dependent membrane fragmentation can only be observed in their presence. These results provide insights into the toxicity of Aβ and may aid in the design of specific compounds to alleviate the neurodegeneration of Alzheimer's disease.

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    • "As depicted in the Figure 8B, Crystallin aggregates of 6 μM incubated with HepG2 cell lines were able to generate ROS, which might be involved in the biological toxicity of the lens protein fibrils. The interaction of various types of aggregates with cell membranes might be leading to the production of ROS, which then disrupts the membrane and other biomolecules, paving the way for aggregates into the interior of the cell (Michele et al., 2012). All these processes then lead to the destruction and death of the cell. "
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    Full-text · Article · Sep 2015 · Journal of Molecular Recognition
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    • "A two-step membrane disruption mechanism was identified recently [34–36]. First, ion-selective channels are formed, then disruption and fragmentation of the membrane occurs during fibril formation, a process that is aggravated by gangliosides [34]. Membrane disruption has also been reported for other proteins such as islet amyloid polypeptide [37] [38]. "
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    ABSTRACT: Protein aggregation is a hallmark of many neurodegenerative disorders. Alzheimer's disease (AD) is directly linked to deposits of amyloid-β (Aβ) derived from the amyloid-β protein precursor (AβPP), and multiple experimental studies have investigated the aggregation behavior of these amyloids. The present paper reports modeling of the aggregation propensities and cell toxicities of genetic variants of Aβ known to increase disease risk. From correlation to experimental data, and using four distinct experimental structures to test structural sensitivity, we find that the Spatial Aggregation Propensity (SAP) formalism can describe the relative experimental aggregation propensities of Aβ 42 variants (R2 = 0.49 and 0.70, p∼0.02 and 0.002, for 1IYT and 1Z0Q conformations using a probe radius of 10 Å). Our analysis finds correlation between the reduction in hydrophilic surface and experimental aggregation propensities. Finally, we show that experimental cell toxicities of Aβ variants are well described by computed SAP values, suggesting direct interplay between aggregation propensity and cell toxicity and providing a step toward a first computational estimator of Aβ toxicity. The present study contributes to our understanding of amyloid aggregation and suggests a method to predict aggregation propensity and toxicity of Aβ variants, and potentially to reduce aggregation propensities of amyloids by molecular intervention directed toward specific conformations of the peptides.
    Full-text · Article · Apr 2015 · Journal of Alzheimer's disease: JAD
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    • "Taken together, these data strongly suggested that the AMP properties of Ab 1-42 differed significantly from those of LL-37 and further suggested that Ab 1-42 initiated its anti-viral effects prior to HSV-1 entry into the cells. Studies using model membranes (Jang et al. 2013; Masters and Selkoe 2012; Zhao et al. 2012; Sciacca et al. 2012), human neurons and mouse fibroblasts (Jang et al. 2010) have shown that Ab peptides can insert into lipid bilayers and form toxic ion channels that destabilize cellular ionic balance. Therefore, we tested the possibility that this mechanism could explain the anti-viral activity of Ab peptides. "
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    ABSTRACT: Amyloid plaques, the hallmark of Alzheimer's disease (AD), contain fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1) has been implicated as a risk factor for AD and found to co-localize within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial, anti-yeast and anti-viral activities. Here, fibroblast, epithelial and neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1 replication when added 2 h prior to or concomitantly with virus challenge, but not when added 2 or 6 h after virus addition. In contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the non-enveloped human adenovirus. In comparison, antimicrobial peptide LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1 in a cell-free system and prevented viral entry into cells. The sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1 envelope. Our data suggest that Aβ peptides represent a novel class of antimicrobial peptides that protect against neurotropic enveloped virus infections such as HSV-1. Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.
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Questions & Answers about this publication

  • Jeffrey R Brender added an answer in Amyloid Beta-Peptides:
    Amyloid beta peptide (22-35), (16-22). How are these fragments biologically relevant?
    In literature interaction of Amyloid beta peptide with membrane sometimes attributed to the fragments (22-35) or (16-22). As they are the transmembrane components of the peptide. Assuming that, I am wondering about biological relevance of these fragments compare to the whole peptide (1-40, 1-42)?
    Jeffrey R Brender
    If you are working with membrane disruption by Abeta you may want to look at this paper:
    https://www.researchgate.net/publication/230796871_Two-Step_Mechanism_of_Membrane_Disruption_by_A_through_Membrane_Fragmentation_and_Pore_Formation
    For general information on amyloids you want to look at this thread and join the project associated with it:
    https://www.researchgate.net/post/Amyloid_protocols_project
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      [Show abstract] [Hide abstract]
      ABSTRACT: Disruption of cell membranes by Aβ is believed to be one of the key components of Aβ toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by Aβ occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addition of freshly dissolved Aβ(1-40), defects form on the membrane that share many of the properties of Aβ channels originally reported from single-channel electrical recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we observed that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved Aβ(1-40) is weakly observed in the absence of gangliosides, fiber-dependent membrane fragmentation can only be observed in their presence. These results provide insights into the toxicity of Aβ and may aid in the design of specific compounds to alleviate the neurodegeneration of Alzheimer's disease.
      Full-text · Article · Aug 2012 · Biophysical Journal