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Recent data have revealed that soluble oligomeric amyloid-beta peptide (Abeta) may be the proximate effectors of neuronal injuries and death in Alzheimer's disease (AD) by unknown mechanisms. Consistently, we recently demonstrated the critical role of a redox-sensitive cytosolic calcium-dependent phospholipase A2 (cPLA2)-arachidonic acid (AA) pathway in Abeta oligomer-induced cell death. According to the involvement of oxidative stress and polyunsaturated fatty acids like AA in the regulation of sphingomyelinase (SMase) activity, the present study underlines the role of SMases in soluble Abeta-induced apoptosis. Soluble Abeta oligomers induced the activation of both neutral and acidic SMases, as demonstrated by the direct measurement of their enzymatic activities, by the inhibitory effects of both specific neutral and acidic SMase inhibitors, and by gene knockdown using antisense oligonucleotides. Furthermore, soluble Abeta-mediated activation of SMases and subsequent cell death were found to be inhibited by antioxidant molecules and a cPLA2-specific inhibitor or antisense oligonucleotide. We also demonstrate that sphingosine-1-phosphate is a potent neuroprotective factor against soluble Abeta oligomer-induced cell death and apoptosis by inhibiting soluble Abeta-induced activation of acidic sphingomyelinase. These results suggest that Abeta oligomers induce neuronal death by activating neutral and acidic SMases in a redox-sensitive cPLA2-AA pathway.

A growing body of evidence supports the notion that soluble oligomers of amyloid-beta (Abeta) peptide interact with the neuronal plasma membrane, leading to cell injury and inducing death-signalling pathways that could account for the increased neurodegeneration occurring in Alzheimer's disease (AD). Docosahexaenoic acid (DHA, C22:6, n-3) is an essential polyunsaturated fatty acid in the CNS and has been shown in several epidemiological and in vivo studies to have protective effects against AD and cognitive alterations. However, the molecular mechanisms involved remain unknown. We hypothesized that DHA enrichment of plasma membranes could protect neurones from apoptosis induced by soluble Abeta oligomers. DHA pre-treatment was observed to significantly increase neuronal survival upon Abeta treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting extracellular signal-related kinase (ERK)-related survival pathways. These data suggest that DHA enrichment probably induces changes in neuronal membrane properties with functional outcomes, thereby increasing protection from soluble Abeta oligomers. Such neuroprotective effects could be of major interest in the prevention of AD and other neurodegenerative diseases.

Abstract: N-terminal-truncated forms of amyloid-β (Aβ) peptide have been recently suggested to play a pivotal role early in Alzheimer''s disease (AD). Among them, Aβ3(pE)-42 peptide, starting with pyroglutamyl at residue Glu-3, is considered as the predominant Aβ species in AD plaques and pre-amyloid lesions. Its abundance is reported to be directly proportional to the severity of the clinical phenotype. The present study investigates the effects of soluble oligomeric Aβ3(pE)-42 after intracerebroventricular injection on mice learning ability and the molecular mechanisms of its in vitro neurotoxicity. Mice injected with soluble Aβ3(pE)-42 or Aβ(l-42) displayed impaired spatial working memory and delayed memory acquisition in Y-maze and Morris water maze tests, while those injected with soluble Aβ(42-1) showed no effect. These cognitive alterations were associated with free radical overproduction in the hippocampus and olfactory bulbs, but not in the cerebral cortex or cerebellum. In vitro, Aβ3(pE)-42 oligomers induced a redox-sensitive neuronal apoptosis involving caspase activation and an arachidonic acid-dependent pro-inflammatory pathway. These data suggest that Aβ3(pE)-42 could mediate the neurodegenerative process and subsequent cognitive alteration occurring in preclinical AD stages. [Copyright &y& Elsevier]

A growing body of evidence supports the notion that soluble oligomers of amyloid-β (Aβ) peptide interact with the neuronal plasma membrane, leading to cell injury and inducing death-signalling pathways that could account for the increased neurodegeneration occurring in Alzheimer's disease (AD). Docosahexaenoic acid (DHA, C22:6, n-3) is an essential polyunsaturated fatty acid in the CNS and has been shown in several epidemiological and in vivo studies to have protective effects against AD and cognitive alterations. However, the molecular mechanisms involved remain unknown. We hypothesized that DHA enrichment of plasma membranes could protect neurones from apoptosis induced by soluble Aβ oligomers. DHA pre-treatment was observed to significantly increase neuronal survival upon Aβ treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting extracellular signal-related kinase (ERK) -related survival pathways. These data suggest that DHA enrichment probably induces changes in neuronal membrane properties with functional outcomes, thereby increasing protection from soluble Aβ oligomers. Such neuroprotective effects could be of major interest in the prevention of AD and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract: Recent data have revealed that soluble oligomeric amyloid-β peptide (Aβ) may be the proximate effectors of neuronal injuries and death in Alzheimer''s disease (AD) by unknown mechanisms. Consistently, we recently demonstrated the critical role of a redox-sensitive cytosolic calcium-dependent phospholipase A2 (cPLA2)-arachidonic acid (AA) pathway in Aβ oligomer-induced cell death. According to the involvement of oxidative stress and polyunsaturated fatty acids like AA in the regulation of sphingomyelinase (SMase) activity, the present study underlines the role of SMases in soluble Aβ-induced apoptosis. Soluble Aβ oligomers induced the activation of both neutral and acidic SMases, as demonstrated by the direct measurement of their enzymatic activities, by the inhibitory effects of both specific neutral and acidic SMase inhibitors, and by gene knockdown using antisense oligonucleotides. Furthermore, soluble Aβ-mediated activation of SMases and subsequent cell death were found to be inhibited by antioxidant molecules and a cPLA2-specific inhibitor or antisense oligonucleotide. We also demonstrate that sphingosine-1-phosphate is a potent neuroprotective factor against soluble Aβ oligomer-induced cell death and apoptosis by inhibiting soluble Aβ-induced activation of acidic sphingomyelinase. These results suggest that Aβ oligomers induce neuronal death by activating neutral and acidic SMases in a redox-sensitive cPLA2-AA pathway. [Copyright &y& Elsevier]

Abstract: Soluble beta-amyloid (Aβ) 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 Aβ oligomers activate cytosolic phospholipase A2 (cPLA2), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of Aβ oligomers in wild type mice. We further demonstrated that the Aβ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA2 −/− mice. Interestingly, expression of the Aβ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA2 −/− mice, but the relationship with the resistance of these mice to the Aβ oligomer toxicity requires further investigation. These results therefore show that cPLA2 plays a key role in the Aβ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer''s disease. [Copyright &y& Elsevier]