Cholesterol-dependent Formation of GM1 Ganglioside-bound Amyloid β-Protein, an Endogenous Seed for Alzheimer Amyloid

Kakio, Atsuko; Nishimoto, Sei‐ichi; Yanagisawa, Katsuhiko; Kozutsumi, Yasunori; Matsuzaki, Katsumi

doi:10.1074/jbc.m100252200

Cited by 376 publications

(445 citation statements)

References 48 publications

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“…Therefore, the interaction of N-terminal region of hIAPP with the membranes would be mediated by gangliosides, which are major anionic lipids of mammalian cell membranes. Gangliosides in lipid rafts are clustered [36] and the local electrostatic interaction with hIAPP would be significantly enhanced. These findings possibly indicate the existence of two independent processes.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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

Wakabayashi¹,

Matsuzaki²

2009

FEBS Letters

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“…There are many examples of the role of valency in adhesion of ligands to multivalent materials [48][49][50][51][52][53]. More specific to Aβ, others have shown for biological membranes that Aβ binding affinity to sialic acid containing gangliosides increased in clustered or multivalent regions of the membrane compared to membrane regions where sialic acids or gangliosides were unclustered [25,30].…”

Section: Discussionmentioning

confidence: 99%

“…Aβ has higher affinity for gangliosides which are clustered and gangliosides containing multiple sialic acids, than it does for other glycolipids [9,[28][29][30]. Based on these findings, we hypothesized that we could develop a membrane mimic that was multivalent in sialic acids, that would bind Aβ, thus sequestering it, making the Aβ unavailable for cell binding, thereby reducing its neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

2008

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Abstractβ-Amyloid peptide (Aβ), the primary protein component in senile plaques associated with Alzheimer's disease (AD), has been implicated in neurotoxicity associated with AD. Previous studies have shown that the Aβ-neuronal membrane interaction plays a crucial role in Aβ toxicity. More specifically, it is thought that Aβ interacts with ganglioside rich and sialic acid rich regions of cell surfaces. In light of such evidence, we have hypothesized that the Aβ-membrane sialic acid interaction could be inhibited through use of a biomimic multivalent sialic acid compound that would compete with the cell surface for Aβ binding. To explore this hypothesis, we synthesized a series of photocrosslinked sialic acid containing oligosaccharides and tested their ability to bind Aβ and attenuate Aβ toxicity in cell culture assays. We show that a polymer prepared via the photocrosslinking of disialyllacto-N-tetraose (DSLNT) was able to attenuate Aβ toxicity at low micromolar concentrations without adversely affecting the cell viability. Polymers prepared from mono-sialyl-oligosaccharides were less effective at Aβ toxicity attenuation. These results demonstrate the feasibility of using photocrosslinked sialyl-oligosaccharides for prevention of Aβ toxicity in vitro and may provide insight into the design of new materials for use in attenuation of Aβ toxicity associated with AD.

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“…Sialic acid is one of many sugars that make up the glycolipids and glycoproteins on a cell surface. Aβ has been shown to have a high affinity for sialic acid containing gangliosides [7,29,[53][54][55][56][57][58] and multivalent sialic acid polymers [18]. Thus, by functionalizing the nanoshell film with sialic acid, we are attempting to mimic the cell surface to create a platform to induce specific binding of Aβ.…”

Section: Introductionmentioning

confidence: 99%

Application of Surface-Enhanced Raman Spectroscopy for Detection of Beta Amyloid Using Nanoshells

et al. 2007

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Currently, no methods exist for the definitive diagnosis of AD premortem. β-amyloid, the primary component of the senile plaques found in patients with this disease, is believed to play a role in its neurotoxicity. We are developing a nanoshell substrate, functionalized with sialic acid residues to mimic neuron cell surfaces, for the surface-enhanced Raman detection of β-amyloid. It is our hope that this sensing mechanism will be able to detect the toxic form of β-amyloid, with structural and concentration information, to aid in the diagnosis of AD and provide insight into the relationship between β-amyloid and disease progression. We have been successfully able to functionalize the nanoshells with the sialic acid residues to allow for the specific binding of β-amyloid to the substrate. We have also shown that a surface-enhanced Raman spectroscopy response using nanoshells is stable and concentrationdependent with detection into the picomolar range.

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Cholesterol-dependent Formation of GM1 Ganglioside-bound Amyloid β-Protein, an Endogenous Seed for Alzheimer Amyloid

Cited by 376 publications

References 48 publications

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

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

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

Application of Surface-Enhanced Raman Spectroscopy for Detection of Beta Amyloid Using Nanoshells

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