Cell membrane changes in brains manifesting senile plaques: an immunohistochemical study of GM1 membranous ganglioside

Iwamoto, Norihiko; Suzuki, Yasuo; Makino, Yutaka; Haga, Chie; Kosaka, Kenji; Iizuka, Ryo

doi:10.1016/0006-8993(90)91592-5

Cited by 14 publications

(10 citation statements)

References 16 publications

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“…The formation and gradual deposition of insoluble β‐amyloid fibrils is suggested to have a causative role in the development of AD (Selkoe 1994), and gangliosides, in particular GM1, have been suggested to be involved in the conversion of soluble non‐toxic β‐amyloid protein to the non‐soluble neurotoxic β‐sheet Aβ variant form. In vitro studies (Iwamoto et al . 1990; Yanagisawa et al .…”

Section: Discussionmentioning

confidence: 99%

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Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent‐resistant membrane domains

Molander-Melin

Blennow

Bogdanović

et al. 2004

Journal of Neurochemistry

201

166

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The formation of neurotoxic beta-amyloid fibrils in Alzheimer's disease (AD) is suggested to involve membrane rafts and to be promoted, in vitro, by enriched concentrations of gangliosides, particularly GM1, and the cholesterol therein. In our study, the presence of rafts and their content of the major membrane lipids and gangliosides in the temporal cortex, reflecting late stages of AD pathology, and the frontal cortex, presenting earlier stages, has been investigated. Whole tissue and isolated detergent-resistant membrane fractions (DRMs) were analysed from 10 AD and 10 age-matched control autopsy brains. DRMs from the frontal cortex of AD brains contained a significantly higher concentration (lmol/lmol glycerophospholipids), of ganglioside GM1 (22.3 ± 4.6 compared to 10.3 ± 6.4, p < 0.001) and GM2 (2.5 ± 1.0 compared to 0.55 ± 0.3, p < 0.001). Similar increases of these gangliosides were also seen in DRMs from the temporal cortex of AD brains, which, in addition, comprised significantly lower proportions of DRMs. Moreover, these remaining rafts were depleted in cholesterol (from 1.5 ± 0.2 to 0.6 ± 0.3 lmol/lmol glycerophospholipids, p < 0.001). In summary, we found an increased proportion of GM1 and GM2 in DRMs, and accelerating plaque formation at an early stage, which may gradually lead to membrane raft disruptions and thereby affect cellular functions associated with the presence of such membrane domains.

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Section: Discussionmentioning

confidence: 99%

“…1991a,b). The major brain ganglioside structures, and in particular GM1, have been found to bind to the Aβ peptide (Iwamoto et al . 1990; Yanagisawa et al .…”

mentioning

confidence: 99%

Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent‐resistant membrane domains

Molander-Melin

Blennow

Bogdanović

et al. 2004

Journal of Neurochemistry

201

166

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“…For example, an antibody that binds a specific glycan by immunoassay may apparently be unable to bind the same ganglioside when present in an intact membrane (23). Furthermore, different anti-GM1 antibodies can have very different binding patterns in the CNS (24,25). In addition to differences in antibody affinities, one explanation for such discrepancies might be that, within the complex environment of glycolipid-enriched microdomains, the interacting oligosaccharide headgroup is masked from the protein binding partner by surrounding molecules.…”

Section: Introductionmentioning

confidence: 99%

The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice

Greenshields¹,

Halstead²,

Zitman³

et al. 2009

J. Clin. Invest.

104

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Anti-GM1 ganglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse monoclonal anti-GM1 antibodies to probe the GM1-rich motor nerve terminal membrane in mice, we here show that the antigenic oligosaccharide of GM1 in the live plasma membrane is cryptic, hidden on surface domains that become buried for a proportion of anti-GM1 antibodies due to a masking effect of neighboring gangliosides. The cryptic GM1 binding domain was exposed by sialidase treatment that liberated sialic acid from masking gangliosides including GD1a or by disruption of the live membrane by freezing or fixation. This cryptic behavior was also recapitulated in solid-phase immunoassays. These data show that certain anti-GM1 antibodies exert potent complement activation-mediated neuropathogenic effects, including morphological damage at living terminal motor axons, leading to a block of synaptic transmission. This occurred only when GM1 was topologically available for antibody binding, but not when GM1 was cryptic. This revised understanding of the complexities in ganglioside membrane topology provides a mechanistic account for wide variations in the neuropathic potential of anti-GM1 antibodies.

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“…GM1 is present in substantial amounts in the brain [38], predominantly in myelin and astrocytes [39,40,41,42,43] but also in neurons [43,44,45]. It has been suggested that the binding of Aβ to GM1 acts as a seed and converts the peptide to its toxic form of β-sheet structure, thereby facilitating the formation of amyloid fibrils [46,47].…”

Section: Introductionmentioning

confidence: 99%

Altered Distribution of the Gangliosides GM1 and GM2 in Alzheimer’s Disease

Pernber

Blennow

Bogdanović

et al. 2012

Dement Geriatr Cogn Disord

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Background: Alzheimer’s disease (AD) is a neurodegenerative disorder where β-amyloid tends to aggregate and form plaques. Lipid raft-associated ganglioside GM1 has been suggested to facilitate β-amyloid aggregation; furthermore, GM1 and GM2 are increased in lipid rafts isolated from cerebral cortex of AD cases. Aim/Method: The distribution of GM1 and GM2 was studied by immunohistochemistry in the frontal and temporal cortex of AD cases. Frontotemporal dementia (FTD) was included as a contrast group. Results: The distribution of GM1 and GM2 changes during the process of AD (n = 5) and FTD (n = 3) compared to controls (n = 5). Altered location of the GM1-positive small circular structures seems to be associated with myelin degradation. In the grey matter, the staining of GM1-positive plasma membranes might reflect neuronal loss in the AD/FTD tissue. The GM1-positive compact bundles were only visible in cells located in the AD frontal grey matter, possibly reflecting raft formation of GM1 and thus a pathological connection. Furthermore, our results suggest GM2 to be enriched within vesicles of pyramidal neurons of the AD/FTD brain. Conclusion: Our study supports the biochemical finding of ganglioside accumulation in cellular membranes of AD patients and shows a redistribution of these molecules.

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Cell membrane changes in brains manifesting senile plaques: an immunohistochemical study of GM1 membranous ganglioside

Cited by 14 publications

References 16 publications

Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent‐resistant membrane domains

Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent‐resistant membrane domains

The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice

Altered Distribution of the Gangliosides GM1 and GM2 in Alzheimer’s Disease

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