Fluorescence microscopy studies on islet amyloid polypeptide fibrillation at heterogeneous and cellular membrane interfaces and its inhibition by resveratrol

Radovan, Diana; Opitz, N.; Winter, Roland

doi:10.1016/j.febslet.2009.03.059

Cited by 62 publications

(71 citation statements)

References 39 publications

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“…That resveratrol promotes high molecular weight aggregation in- stead of disassembling soluble and insoluble A␤ conformers into low molecular weight species is contrary to conventional wisdom. However, this observation is supported by a few disparate reports for resveratrol and other polyphenols (57,58,60,63,91,92), as well as the broader literature demonstrating that many small molecules and peptides redirect the aggregation cascade instead of inhibiting it completely (40,56,62,(93)(94)(95)(96). For example, the aggregation of monomeric A␤ and ␣-synuclein was studied in the presence of EGCG.…”

Section: Discussionmentioning

confidence: 67%

Resveratrol Selectively Remodels Soluble Oligomers and Fibrils of Amyloid Aβ into Off-pathway Conformers

Ladiwala

Lin

Bale

et al. 2010

Journal of Biological Chemistry

280

301

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Misfolded proteins associated with diverse aggregation disorders assemble not only into a single toxic conformer but rather into a suite of aggregated conformers with unique biochemical properties and toxicities. To what extent small molecules can target and neutralize specific aggregated conformers is poorly understood. Therefore, we have investigated the capacity of resveratrol to recognize and remodel five conformers (monomers, soluble oligomers, non-toxic oligomers, fibrillar intermediates, and amyloid fibrils) of the A␤1-42 peptide associated with Alzheimer disease. We find that resveratrol selectively remodels three of these conformers (soluble oligomers, fibrillar intermediates, and amyloid fibrils) into an alternative aggregated species that is non-toxic, high molecular weight, and unstructured. Surprisingly, resveratrol does not remodel non-toxic oligomers or accelerate A␤ monomer aggregation despite that both conformers possess random coil secondary structures indistinguishable from soluble oligomers and significantly different from their ␤-sheet rich, fibrillar counterparts. We expect that resveratrol and other small molecules with similar conformational specificity will aid in illuminating the conformational epitopes responsible for A␤-mediated toxicity.Despite the remarkable fidelity of protein folding in diverse cellular environments, defects do occur that are linked to an array of protein aggregation diseases. In many such disorders (e.g. Alzheimer (1-4), Parkinson (5, 6), Huntington (7-9), and Prion (10, 11) diseases) specific peptides of unrelated sequence aggregate into similar types of assemblies ranging from soluble, low molecular weight oligomers to insoluble, high molecular weight amyloid fibrils (1, 12).A particularly intriguing aspect of protein misfolding is that a single polypeptide chain can adopt multiple aggregated conformations with unique biological activities (13). Such conformational diversity was first observed for the mammalian prion protein PrP (14 -21). Different infectious prion conformations of PrP, known as strains or variants, encipher unique prion diseases through differences in their aggregate structure (14,16,19,(22)(23)(24). More recently, polymorphic aggregate structures have been formed in vitro and identified in vivo for many other proteins (25-39). However, the biological consequence of such conformational diversity and which conformers are most toxic remains poorly defined.Aggregated A␤ conformers associated with Alzheimer disease also display such conformational diversity (30,32,33,38,40). The A␤ peptide self-assembles through multiple pathways in which several intermediates are transiently populated (41-46). These conformers, which range from dimers and soluble oligomers to fibrillar oligomers and protofibrils, are typically classified either by size or structure. Even though size is an important characteristic of different A␤ conformers, it is now clear that aggregates of the same size can have unique structures (44, 47). These recent findings have been illumi...

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Section: Discussionmentioning

confidence: 67%

Resveratrol Selectively Remodels Soluble Oligomers and Fibrils of Amyloid Aβ into Off-pathway Conformers

Ladiwala

Lin

Bale

et al. 2010

Journal of Biological Chemistry

280

301

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“…Recently, the uptake of membrane lipids of pancreatic b-cell line INS-1E during the aggregation of hIAPP was also reported [27]. In the case of Alzheimer's amyloid b-protein, ganglioside-bound form promotes the protein aggregation and cytotoxicity [28].…”

Section: Resultsmentioning

confidence: 98%

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Wakabayashi¹,

Matsuzaki²

2009

FEBS Letters

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Edited by Jesus Avila Keywords:Human islet amyloid polypeptide Amyloid fibril Ganglioside Cholesterol Lipid raft a b s t r a c t Human islet amyloid polypeptide (hIAPP) is the primary component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus. However, it is unknown how amyloid fibrils are formed in vivo. In this study, we demonstrate that gangliosides play an essential role in the formation of amyloid deposits by hIAPP on plasma membranes. Amyloid fibrils accumulated in ganglioside-and cholesterol-rich microscopic domains ('lipid rafts'). The depletion of gangliosides or cholesterol significantly reduced the amount of amyloid deposited. These results clearly showed that the formation of amyloid fibrils was mediated by gangliosides in lipid rafts.

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“…By gradually increasing the temperature, the transition to an all-fluid l d phase was detected at~40 8C in giant unilamellar vesicles (GUVs). [42] For visualization, the fluorescent membrane marker rhodamine-DHPE, which is known to preferentially label the l d phase, was used. C-terminally labeled hIAPP (1-37)-K-Bodipy-FL was added into the system at room temperature.…”

Section: Interaction Of Hiapp With Model Raft Guvs As Determined By Fmentioning

confidence: 99%

Interaction of hIAPP with Model Raft Membranes and Pancreatic β‐Cells: Cytotoxicity of hIAPP Oligomers

et al. 2010

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Type II diabetes mellitus (T2DM) is associated with beta-cell failure, which correlates with the formation of pancreatic islet amyloid deposits. The human islet amyloid polypeptide (hIAPP) is the major component of islet amyloid and undergoes structural changes followed by self-association and pathological tissue deposition during aggregation in T2DM. There is clear evidence that the aggregation process is accelerated in the presence of particular lipid membranes. Whereas hIAPP aggregation has been extensively studied in homogeneous model membrane systems, especially negatively charged lipid bilayers, information on the interaction of hIAPP with heterogeneous model raft membranes has been missing until now. In the present study, we focus on the principles of aggregation and amyloid formation of hIAPP in the presence of model raft membranes. Time-lapse tapping mode AFM and confocal fluorescence microscopy experiments followed membrane permeabilization and localization of hIAPP in the raft membrane. Together with the ThT and WST-1 assay, the data revealed elevated cytotoxicity of hIAPP oligomers on INS-1E cells.

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Fluorescence microscopy studies on islet amyloid polypeptide fibrillation at heterogeneous and cellular membrane interfaces and its inhibition by resveratrol

Cited by 62 publications

References 39 publications

Resveratrol Selectively Remodels Soluble Oligomers and Fibrils of Amyloid Aβ into Off-pathway Conformers

Resveratrol Selectively Remodels Soluble Oligomers and Fibrils of Amyloid Aβ into Off-pathway Conformers

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Interaction of hIAPP with Model Raft Membranes and Pancreatic β‐Cells: Cytotoxicity of hIAPP Oligomers

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