Gangliosides determine the amyloid pathology of Alzheimer's disease

Oikawa, Naoto; Yamaguchi, Hideyo; Ogino, Kōichi; Taki, Takao; Yuyama, Ken‐ichi; Yamamoto, Naoki; Shin, Ryong-Woon; Furukawa, Koichi; Yanagisawa, Katsuhiko

doi:10.1097/wnr.0b013e32832e4b9d

Cited by 61 publications

(44 citation statements)

References 21 publications

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“…35 Gangliosides are critical for neuronal integrity and plasticity 36 and synaptic function, 37 and have been involved in several neurodegenerative disorders, including Alzheimer's disease. 38,39 Circular dichroism experiments showed that GM1 can interact with α-syn and inhibit its fibrillation. 18 Consistent with these data, we also found an interaction between GM1 monolayers and α-syn, although we found GM3 to be more effective than GM1 in our assay.…”

Section: Discussionmentioning

confidence: 99%

Altered Ion Channel Formation by the Parkinson's-Disease-Linked E46K Mutant of α-Synuclein Is Corrected by GM3 but Not by GM1 Gangliosides

Pasquale

Fantini

Chahinian

et al. 2010

Journal of Molecular Biology

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Section: Discussionmentioning

confidence: 99%

Altered Ion Channel Formation by the Parkinson's-Disease-Linked E46K Mutant of α-Synuclein Is Corrected by GM3 but Not by GM1 Gangliosides

Pasquale

Fantini

Chahinian

et al. 2010

Journal of Molecular Biology

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“…Considering its high affinity for gangliosides in their natural lipid environment, the chimeric α-syn/HH peptide may have potential therapeutic applications in infectious and neurodegenerative diseases involving gangliosides [2], [4], [12], [18], [20], [38], [39]. It is noteworthy that the pair of histidine residues His-13 and His-14 has been previously identified as a potential target for inhibition of Aβ toxicity [40].…”

Section: Discussionmentioning

confidence: 99%

“…In the human brain, the expression of GM1 gradually increases with age, whereas in parallel GM3 content diminishes [17]. Both GM1 and GM3 have been involved in the pathophysiology of Alzheimer's and Parkinson's diseases [18]–[20]. For all these reasons, it is of high interest to understand how amyloid proteins interact with brain glycolipids.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Glycolipid Code of Alzheimer's and Parkinson's Amyloid Proteins Allowed the Creation of a Universal Ganglioside-Binding Peptide

Yahi

Fantini

2014

PLoS ONE

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A broad range of microbial and amyloid proteins interact with cell surface glycolipids which behave as infectivity and/or toxicity cofactors in human pathologies. Here we have deciphered the biochemical code that determines the glycolipid-binding specificity of two major amyloid proteins, Alzheimer's β-amyloid peptide (Aβ) and Parkinson's disease associated protein α-synuclein. We showed that both proteins interact with selected glycolipids through a common loop-shaped motif exhibiting little sequence homology. This 12-residue domain corresponded to fragments 34-45 of α-synuclein and 5-16 of Aβ. By modulating the amino acid sequence of α-synuclein at only two positions in which we introduced a pair of histidine residues found in Aβ, we created a chimeric α-synuclein/Aβ peptide with extended ganglioside-binding properties. This chimeric peptide retained the property of α-synuclein to recognize GM3, and acquired the capacity to recognize GM1 (an Aβ-inherited characteristic). Free histidine (but not tryptophan or asparagine) and Zn2+ (but not Na+) prevented this interaction, confirming the key role of His-13 and His-14 in ganglioside binding. Molecular dynamics studies suggested that the chimeric peptide recognized cholesterol-constrained conformers of GM1, including typical chalice-shaped dimers, that are representative of the condensed cholesterol-ganglioside complexes found in lipid raft domains of the plasma membrane of neural cells. Correspondingly, the peptide had a particular affinity for raft-like membranes containing both GM1 and cholesterol. The chimeric peptide also interacted with several other gangliosides, including major brain gangliosides (GM4, GD1a, GD1b, and GT1b) but not with neutral glycolipids such as GlcCer, LacCer or asialo-GM1. It could inhibit the binding of Aβ1-42 onto neural SH-SY5Y cells and did not induce toxicity in these cells. In conclusion, deciphering the glycolipid code of amyloid proteins allowed us to create a universal ganglioside-binding peptide of only 12-residues with potential therapeutic applications in infectious and neurodegenerative diseases that involve cell surface gangliosides as receptors.

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“…For some hereditary Aβ variants, aggregation was accelerated in the presence of GM3 and GD3, the main gangliosides expressed in the cerebrovascular basement membrane [269][270][271]. On the other hand, amyloid deposition is significantly increased in the vascular tissue in brains of GM2 synthase KO mice, suggesting that ganglioside-mediated deposition of amyloid is relevant to AD-associated angiopathy as well [272].…”

Section: Sphingolipid Storage Diseasesmentioning

confidence: 96%

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

et al. 2010

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Sphingolipids are polar membrane lipids present as minor components in eukaryotic cell membranes. Sphingolipids are highly enriched in nervous cells, where they exert important biological functions. They deeply affect the structural and geometrical properties and the lateral order of cellular membranes, modulate the function of several membrane-associated proteins, and give rise to important intra- and extracellular lipid mediators. Sphingolipid metabolism is regulated along the differentiation and development of the nervous system, and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system: sphingolipids in the nervous system participate to several signaling pathways controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and synaptic transmission, and neuron-glia interactions, including the formation and stability of central and peripheral myelin. In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal sphingolipid patterns and altered membrane organization that participate to several events related to the pathogenesis of these diseases. The most impressive consequence of this deregulation is represented by anomalous sphingolipid-protein interactions that are at least, in part, responsible for the misfolding events that cause the fibrillogenic and amyloidogenic processing of disease-specific protein isoforms, such as amyloid beta peptide in Alzheimer's disease, huntingtin in Huntington's disease, alpha-synuclein in Parkinson's disease, and prions in transmissible encephalopathies. Targeting sphingolipid metabolism represents today an underexploited but realistic opportunity to design novel therapeutic strategies for the intervention in these diseases.

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Gangliosides determine the amyloid pathology of Alzheimer's disease

Cited by 61 publications

References 21 publications

Altered Ion Channel Formation by the Parkinson's-Disease-Linked E46K Mutant of α-Synuclein Is Corrected by GM3 but Not by GM1 Gangliosides

Altered Ion Channel Formation by the Parkinson's-Disease-Linked E46K Mutant of α-Synuclein Is Corrected by GM3 but Not by GM1 Gangliosides

Deciphering the Glycolipid Code of Alzheimer's and Parkinson's Amyloid Proteins Allowed the Creation of a Universal Ganglioside-Binding Peptide

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

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