Membrane cholesterol interferes with neuronal apoptosis induced by soluble oligomers but not fibrils of the amyloid‐β peptide

Sponne, Isabelle; Fifre, Alexandre; Kriem, Badreddine; Koziel, Violette; Bihain, Bernard E.; Oster, Thierry; Olivier, Jean‐Luc; Pillot, Thierry

doi:10.1096/fj.03-0372fje

Cited by 84 publications

(89 citation statements)

References 57 publications

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“…Very recently, Pillot and colleagues have also demonstrated that ASM was activated when rat cortical neurons were incubated with Aβ oligomers (Malaplate-Armand et al, 2006). The conflicting data with ASM and NSM implys that different molecular mechanisms and cellular targets may be involved in the neuronal apoptosis and cell death induced by soluble oligomers versus fibrillar Aβ (Sponne et al, 2004;White et al, 2005). These differences also may be due to the different cell types and culture conditions used.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of sphingolipid metabolism in Alzheimer's disease

Huang²,

Li³

et al. 2010

Neurobiology of Aging

449

468

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Abnormal sphingolipid metabolism has been previously reported in Alzheimer's disease (AD). To extend these findings, several sphingolipids and sphingolipid hydrolases were analyzed in brain samples from AD patients and age-matched normal individuals. We found a pattern of elevated acid sphingomyelinase (ASM) and acid ceramidase (AC) expression in AD, leading to a reduction in sphingomyelin and elevation of ceramide. More sphingosine also was found in the AD brains, although sphingosine-1-phosphate (S1P) levels were reduced. Notably, significant correlations were observed between the brain ASM and S1P levels and the levels of amyloid beta peptide (Aβ) and phosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with Aβ oligomers, which were found to activate ASM, increase ceramide, and induce apoptosis. Pretreatment of the neurons with purified, recombinant AC prevented the cells from undergoing Aβ-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to Aβ deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of S1P in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Deregulation of sphingolipid metabolism in Alzheimer's disease

Huang²,

Li³

et al. 2010

Neurobiology of Aging

449

468

View full text Add to dashboard Cite

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“…There is increasing evidence linking altered cholesterol levels in the brain with AD (for review, see Ref. 59) and the viability of A␤-treated neurons in culture (58). The EPR and structural data suggest that A␤M35V has an increased affinity for lipids.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Toxicity and Cellular Binding of a Modified Amyloid β Peptide with a Methionine to Valine Substitution

Ciccotosto

Tew

Curtain

et al. 2004

Journal of Biological Chemistry

103

101

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The amyloid ␤ peptide (A␤) is toxic to neuronal cells, and it is probable that this toxicity is responsible for the progressive cognitive decline associated with Alzheimer's disease. However, the nature of the toxic A␤ species and its precise mechanism of action remain to be determined. It has been reported that the methionine residue at position 35 has a pivotal role to play in the toxicity of A␤. We examined the effect of mutating the methionine to valine in A␤42 (A␤M35V). The neurotoxic activity of A␤M35V on primary mouse neuronal cortical cells was enhanced, and this diminished cell viability occurred at an accelerated rate compared with A␤42. A␤M35V binds Cu 2؉ and produces similar amounts of H 2 O 2 as A␤42 in vitro, and the neurotoxic activity was attenuated by the H 2 O 2 scavenger catalase. The increased toxicity of A␤M35V was associated with increased binding of this mutated peptide to cortical cells. The M35V mutation altered the interaction between A␤ and copper in a lipid environment as shown by EPR analysis, which indicated that the valine substitution made the peptide less rigid in the bilayer region with a resulting higher affinity for the bilayer. Circular dichroism spectroscopy showed that both A␤42 and A␤M35V displayed a mixture of ␣-helical and ␤-sheet conformations. These findings provide further evidence that the toxicity of A␤ is regulated by binding to neuronal cells.Genetic evidence derived from early onset cases of Alzheimer's disease (AD) 1 indicated that the metabolism of the amyloid ␤ peptide (A␤) is clearly linked to the pathogenesis of this disease (1). There is a clear correlation found between the levels of soluble A␤, synaptic damage, and cognitive impairment in AD patients (2-4). It is well established that synthetic A␤ is toxic to neuronal cells in culture (5-8). Moreover, naturally secreted oligomers of A␤ can potently inhibit neuronal long term potentiation, a measure of synaptic plasticity in vivo (9,10). Although the precise mechanism of A␤-induced neuronal toxicity remains unclear, the interaction of A␤ with membranes and/or membrane proteins appears to play an important role in A␤-mediated neurotoxicity. Because A␤ contains part of the transmembrane domain of the amyloid precursor protein (APP), it is not surprising that A␤ interacts with cell membranes and lipoproteins. Numerous reports have described the effects of A␤ on membranes and lipid systems and their possible roles in A␤ neurotoxicity. These include changes in membrane fluidity leading to membrane depolarization and disorder (11, 12), pore/channel formation that could affect calcium homeostasis (13-15), and lipid peroxidation via membrane-associated free radical formation (16 -19). A␤ can decrease the fluidity of both artificial unilamellar liposomes and mouse brain membranes (12) and human frontal cortex membranes (11). A␤ has an amplifying effect on cellular calcium signaling. At a low concentration, A␤ acts by stimulating endogenous calcium conductance pathways (20), whereas at higher concentrations A␤ disru...

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“…Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay as previously described (Pillot et al, 1999;Sponne et al, 2004). Cell nuclei were visualized using 4,6-diamidino-2-phenylindole (DAPI) staining (Sponne et al, 2004).…”

Section: Neuronal Viability and Monitoring Of Apoptosismentioning

confidence: 99%

“…Cell nuclei were visualized using 4,6-diamidino-2-phenylindole (DAPI) staining (Sponne et al, 2004). To evaluate the percentage of apoptotic cells, 10 independent fields of microscope were counted (approximately 400 cells) in 3 separate experiments with 3 determinations each (Kriem et al, 2005).…”

Section: Neuronal Viability and Monitoring Of Apoptosismentioning

confidence: 99%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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Soluble beta-amyloid (A␤) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A␤ oligomers activate cytosolic phospholipase A 2 (cPLA 2 ), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA 2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A␤ oligomers in wild type mice. We further demonstrated that the A␤ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA 2 Ϫ/Ϫ mice. Interestingly, expression of the A␤ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA 2 Ϫ/Ϫ mice, but the relationship with the resistance of these mice to the A␤ oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A␤ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.

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Membrane cholesterol interferes with neuronal apoptosis induced by soluble oligomers but not fibrils of the amyloid‐β peptide

Cited by 84 publications

References 57 publications

Deregulation of sphingolipid metabolism in Alzheimer's disease

Deregulation of sphingolipid metabolism in Alzheimer's disease

Enhanced Toxicity and Cellular Binding of a Modified Amyloid β Peptide with a Methionine to Valine Substitution

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

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