An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer’s disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained fromADbrains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid- peptide (A42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca2+ ions induced by A42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by A42 oligomers with low solvent-exposed hydrophobicity (A−) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload / Cascella, Roberta; Evangelisti, Elisa; Bigi, Alessandra; Becatti, Matteo; Fiorillo, Claudia; Stefani, Massimo; Chiti, Fabrizio; Cecchi, Cristina. - In: JOURNAL OF ALZHEIMER'S DISEASE. - ISSN 1387-2877. - ELETTRONICO. - 60:(2017), pp. 923-938. [10.3233/JAD-170340]

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

Roberta Cascella;Elisa Evangelisti;Alessandra Bigi;Matteo Becatti;Claudia Fiorillo;Massimo Stefani;Fabrizio Chiti;Cristina Cecchi
2017

Abstract

An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer’s disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained fromADbrains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid- peptide (A42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca2+ ions induced by A42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by A42 oligomers with low solvent-exposed hydrophobicity (A−) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.
2017
60
923
938
Cascella, Roberta; Evangelisti, Elisa; Bigi, Alessandra; Becatti, Matteo; Fiorillo, Claudia; Stefani, Massimo; Chiti, Fabrizio; Cecchi, Cristina
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1102439
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