Formation of Toxic Fibrils of Alzheimer’s Amyloid β-Protein-(1–40) by Monosialoganglioside GM1, a Neuronal Membrane Component

Okada, Takuma; Wakabayashi, Masaki; Ikeda, Keisuke; Matsuzaki, Katsumi

doi:10.1016/j.jmb.2007.05.069

Cited by 111 publications

(124 citation statements)

References 50 publications

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“…Ab aggregation in brain is accelerated through an increase in the level of GM1 in neuronal membranes (42). Further studies have demonstrated that GM1 and GT1b promote the aggregation and cytotoxicity of Ab1-40, and these gangliosides, especially GM1, catalyze the formation of neurotoxic fibrils (74). The effect is dose dependent; in the presence of lower concentrations of GM1 (about 25 mM), Ab1-40 aggregates much more slowly, indicating that an increase in the concentration of GM1 significantly facilitates the aggregation of Ab.…”

Section: Interaction Of Ab With Gangliosides May Play a Critical Rolementioning

confidence: 99%

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Ariga

McDonald

2008

Journal of Lipid Research

292

236

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Section: Interaction Of Ab With Gangliosides May Play a Critical Rolementioning

confidence: 99%

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Ariga

McDonald

2008

Journal of Lipid Research

292

236

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“…21 While the inserted state of Aβ has been experimentally verified, 18,22,23 the pathway to this state is not addressed here. Our initial protein/lipid structure was one in which the helix of 40-or 42-residue Aβ, denoted Aβ 40 or Aβ 42 , was halfinserted in the extracellular leaflet of the bilayer, modeling a protein that has a non-polar helix or LID and a polar helix immediately after it enters the cis-side of the membrane.…”

Section: Introductionmentioning

confidence: 99%

Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer

Qiu

Buie

Cheng

et al. 2014

The Journal of Chemical Physics

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Protein conformation and orientation in the lipid membrane plays a key role in many cellular processes. Here we use molecular dynamics simulation to investigate the relaxation and C-terminus diffusion of a model helical peptide: beta-amyloid (Aβ) in a lipid membrane. We observed that after the helical peptide was initially half-embedded in the extracelluar leaflet of phosphatidylcholine (PC) or PC/cholesterol (PC/CHOL) membrane, the C-terminus diffused across the membrane and anchored to PC headgroups of the cytofacial lipid leaflet. In some cases, the membrane insertion domain of the Aβ was observed to partially unfold. Applying a sigmoidal fit to the process, we found that the characteristic velocity of the C-terminus, as it moved to its anchor site, scaled with θ u −4/3 , where θ u is the fraction of the original helix that was lost during a helix to coil transition. Comparing this scaling with that of bead-spring models of polymer relaxation suggests that the C-terminus velocity is highly regulated by the peptide helical content, but that it is independent of the amino acid type. The Aβ was stabilized by the attachment of the positive Lys28 side chain to the negative phosphate of PC or 3β oxygen of CHOL in the extracellular lipid leaflet and of the C-terminus to its anchor site in the cytofacial lipid leaflet.

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“…Other studies indicate that hIAPP-induced membrane damage is not specific for ions, but results in membrane leakage of molecules the size of calcein (600 Da), indicating a general membrane disruption mechanism (9,(12)(13)(14)(15). In addition to the hypothesis that oligomers are the toxic species, recent reports suggest that the fibrillar form of amyloidogenic proteins can also be cytotoxic, e.g., fibrillar Abeta1-40 (16), fibrillar prion protein (17), and fibrillar lysozyme (18). Thus, not only is the mechanism of cytotoxic action of amyloidogenic proteins unknown, the nature of the cytotoxic species is still a topic of discussion as well.…”

mentioning

confidence: 99%

Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

Engel

Khemtémourian²,

Kleijer³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

437

482

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Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the insulinproducing islet ␤ cells in type 2 diabetes mellitus. It has been suggested that the mechanism of this ␤ cell death involves membrane disruption by human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid. However, the molecular mechanism of hIAPP-induced membrane disruption is not known. Here, we propose a hypothesis that growth of hIAPP fibrils at the membrane causes membrane damage. We studied the kinetics of hIAPP-induced membrane damage in relation to hIAPP fibril growth and found that the kinetic profile of hIAPP-induced membrane damage is characterized by a lag phase and a sigmoidal transition, which matches the kinetic profile of hIAPP fibril growth. The observation that seeding accelerates membrane damage supports the hypothesis. In addition, variables that are well known to affect hIAPP fibril formation, i.e., the presence of a fibril formation inhibitor, hIAPP concentration, and lipid composition, were found to have the same effect on hIAPP-induced membrane damage. Furthermore, electron microscopy analysis showed that hIAPP fibrils line the surface of distorted phospholipid vesicles, in agreement with the notion that hIAPP fibril growth at the membrane and membrane damage are physically connected. Together, these observations point toward a mechanism in which growth of hIAPP fibrils, rather than a particular hIAPP species, is responsible for the observed membrane damage. This hypothesis provides an additional mechanism next to the previously proposed role of oligomers as the main cytotoxic species of amyloidogenic proteins.amylin ͉ amyloid cytotoxicity ͉ large unilamellar vesicles ͉ protein-membrane interaction ͉ type 2 diabetes mellitus T ype 2 diabetes mellitus (DM2) is characterized histopathologically by the presence of fibrillar amyloid deposits in the pancreatic islets of Langerhans. Amyloid cytotoxicity is thought to be an early mechanism involved in death of insulin-producing islet ␤ cells in DM2 (1). The main component of islet amyloid, and the actual fibril-forming molecule, is a 37-amino acid peptide called human islet amyloid polypeptide (hIAPP) or amylin, which is produced together with insulin in the pancreatic islet ␤-cells. It is thought that ␤ cells of DM2 patients are somehow killed through hIAPP-induced damage of the ␤ cell membrane (2). However, our knowledge of the mechanism of hIAPP-induced membrane damage is extremely sparse. It is not known how cytotoxic hIAPP species interact with cellular membranes and induce cell death. Furthermore, it is not established whether cytotoxic hIAPP species are formed before contacting the membrane or whether a membrane environment is in fact required for the formation of cytotoxic hIAPP species.The prevailing view is that membrane damage and concomitant ␤ cell death are caused by cytotoxic hIAPP oligomers (2-9). There are indications that these oligomers form ion channels (2, 3), as has been suggeste...

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Formation of Toxic Fibrils of Alzheimer’s Amyloid β-Protein-(1–40) by Monosialoganglioside GM1, a Neuronal Membrane Component

Cited by 111 publications

References 50 publications

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer

Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

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