Lipid Rafts Mediate Amyloid-Induced Calcium Dyshomeostasis and Oxidative Stress in Alzheimer’s Disease

Evangelisti, Elisa; Wright, Donna; Zampagni, Mariagioia; Cascella, Roberta; Fiorillo, Claudia; Bagnoli, Silvia; Relini, Annalisa; Nichino, Daniela; Scartabelli, Tania; Nacmias, Benedetta; Sorbi, Sandro; Cecchi, Cristina

doi:10.2174/1567205011310020004

Cited by 47 publications

(37 citation statements)

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“…Hippocampal neurons were maintained in neuronal basal medium (NBM) at 37 • C in a 5.0% CO 2 -humidified atmosphere and analyzed 14 days after plating, as previously described [39]. GM1 enrichment was obtained by supplementing neurons with GM1 from bovine brain (150 g/ml) for 24 h at 37 • C, as previously described [40].…”

Section: Cell Culturementioning

confidence: 99%

“…In a separate set of experiments, the cells with increased GM1 content (100 g/ml) were pre-treated for 10 min on ice with 0.05% trypsin and after washing twice treated for 10 or 60 min at 37 • C with A+ or A-oligomers (12 M, monomer equivalents). In another set of experiments the cells with increased GM1 content (100 g/ml) were pre-treated for 60 Primary rat hippocampal neurons with increased GM1 content (150 g/ml) were treated for 60 min with 12 M (monomer equivalents) A␤ 42 oligomers (A+ or A-) in the absence or in the presence of pre-treatment for 20 min with CTX-B, as previously reported [40].…”

Section: Cytosolic Free Ca 2+ Levelsmentioning

confidence: 99%

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Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

Cascella

Evangelisti

Bigi

et al. 2017

JAD

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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 from AD brains 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 (A␤ 42 ), with intracellular flux of Ca 2+ 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 Ca 2+ ions induced by A␤ 42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by A␤ 42 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 Ca 2+ 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.

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Section: Cell Culturementioning

confidence: 99%

Section: Cytosolic Free Ca 2+ Levelsmentioning

confidence: 99%

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

Cascella

Evangelisti

Bigi

et al. 2017

JAD

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“…Moreover, the same group has demonstrated that modest depletion of GM1 content decreases the interaction of Aβ oligomers with the plasma membrane in fibroblasts of patients with familial Alzheimer's disease and in rat brain cortical neurons, causing a reduction in cytotoxicity (34).…”

Section: Gm1 In Alzheimer's Disease and Other Amyloid Pathologiesmentioning

confidence: 99%

GM1 and GM2 gangliosides: recent developments

Bisel

Pavone

Calamai³

2014

BioMolecular Concepts

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GM1 and GM2 gangliosides are important components of the cell membrane and play an integral role in cell signaling and metabolism. In this conceptual overview, we discuss recent developments in our understanding of the basic biological functions of GM1 and GM2 and their involvement in several diseases. In addition to a well-established spectrum of disorders known as gangliosidoses, such as Tay-Sachs disease, more and more evidence points at an involvement of GM1 in Alzheimer's and Parkinson's diseases. New emerging methodologies spanning from single-molecule imaging in vivo to simulations in silico have complemented standard studies based on ganglioside extraction.

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“…and have been shown to be recruited to lipid rafts (18). ABeta peptide has a high 636 affinity for copper, and Abeta to Abeta--peptide aggregation is stabilized by copper 637 (37).…”

Section: Transmissible Spongiform Encephalopathymentioning

confidence: 99%

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

Reddy

2017

Preprint

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A scientific theory or hypothesis is presented, in which mineral particles may play a pivotal role in the prion disease transmissible spongiform encephalopathy (TSE), and possibly also in other protein--misfolding diseases. Montmorillonite clay (Mte) and other minerals are known to bind to scrapie prion protein (PrP--Sc) in soil. The hypothesis is explored that, in transmissible spongiform encephalopathy, Mte or other mineral particles, upon contact with lipids, such as in the gut or at the cell plasma membrane, may interact with lipids or with lipid rafts. The minerals may catalyze formation of lipid vesicles, and might also be capable of inducing lipid raft clustering or other lipid raft or plasma membrane changes. Some of these lipid vesicles or rafts might then contain or bind PrP--Sc, and sometimes also contain montmorillonite or the mineral catalyst. Mte--PrP--Sc or the affected lipid vesicles/particles could also promote PrP--C to PrP--Sc conversion by providing conditions for misfolding. These conditions provided for protein misfolding may include the following: multiple unique compartments providing sizes, shapes or aqueous/lipid environments that promote varied folding conformations, presence of an anion (Mte), negative--charge (Mte), lipid membrane mimetic (e.g. associated lipid particle, vesicle or raft), interaction with bound or contained PrP--Sc, presence of bound copper, and/or copper binding affinity. Mte--catalyzed lipid vesicles are proto--cell--like entities, making them potential candidates to be part of the infectious particle in prion disease, which can behave like an infectious organism but does not appear to depend on nucleic acid. Lipid vesicles or rafts may resemble endosomes, which would be consistent with reports of prion being transported and formed along an endosome--like pathway. Additionally, the vesicles or rafts could accumulate intra--cellularly, and might form tubulovesicular structures, which are hallmarks of prion disease. Potential applications of this theory to more common protein misfolding diseases, Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, are discussed. This theory, which I term the mineral--lipid prion hypothesis, provides a basis for potential novel interventions in the field of prion and protein--misfolding diseases. In addition, this theory suggests that similar silicate--or mineral--catalyzed lipid vesicles/liposomes might be further explored as useful compartments that could be manipulated in order to deliver molecules or even proteins to or from cells.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2982v1 | CC BY 4.0

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Lipid Rafts Mediate Amyloid-Induced Calcium Dyshomeostasis and Oxidative Stress in Alzheimer’s Disease

Cited by 47 publications

References 1 publication

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

GM1 and GM2 gangliosides: recent developments

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

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