Dietary arachidonic acid increases deleterious effects of amyloid-β oligomers on learning abilities and expression of AMPA receptors: putative role of the ACSL4-cPLA2 balance

International audienceAbstractBackgroundPolyunsaturated fatty acids play a crucial role in neuronal function, and the modification of these compounds in the brain could have an impact on neurodegenerative diseases such as Alzheimer’s disease. Despite the fact that arachidonic acid is the second foremost polyunsaturated fatty acid besides docosahexaenoic acid, its role and the regulation of its transfer and mobilization in the brain are poorly known.MethodsTwo groups of 39 adult male BALB/c mice were fed with an arachidonic acid-enriched diet or an oleic acid-enriched diet, respectively, for 12 weeks. After 10 weeks on the diet, mice received intracerebroventricular injections of either NaCl solution or amyloid-β peptide (Aβ) oligomers. Y-maze and Morris water maze tests were used to evaluate short- and long-term memory. At 12 weeks on the diet, mice were killed, and blood, liver, and brain samples were collected for lipid and protein analyses.ResultsWe found that the administration of an arachidonic acid-enriched diet for 12 weeks induced short-term memory impairment and increased deleterious effects of Aβ oligomers on learning abilities. These cognitive alterations were associated with modifications of expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, postsynaptic density protein 95, and glial fibrillary acidic protein in mouse cortex or hippocampus by the arachidonic acid-enriched diet and Aβ oligomer administration. This diet also led to an imbalance between the main ω-6 fatty acids and the ω-3 fatty acids in favor of the first one in erythrocytes and the liver as well as in the hippocampal and cortical brain structures. In the cortex, the dietary arachidonic acid also induced an increase of arachidonic acid-containing phospholipid species in phosphatidylserine class, whereas intracerebroventricular injections modified several arachidonic acid- and docosahexaenoic acid-containing species in the four phospholipid classes. Finally, we observed that dietary arachidonic acid decreased the expression of the neuronal form of acyl-coenzyme A synthetase 4 in the hippocampus and increased the cytosolic phospholipase A2 activation level in the cortices of the mice.ConclusionsDietary arachidonic acid could amplify Aβ oligomer neurotoxicity. Its consumption could constitute a risk factor for Alzheimer’s disease in humans and should be taken into account in future preventive strategies. Its deleterious effect on cognitive capacity could be linked to the balance between arachidonic acid-mobilizing enzymes

Additional file 7: of Dietary arachidonic acid increases deleterious effects of amyloid-β oligomers on learning abilities and expression of AMPA receptors: putative role of the ACSL4-cPLA2 balance

Modification of hippocampal AMPA receptors induced by ARA diet and Aβ42. Immediately after the probe test, mice were killed, and homogenates were prepared from the hippocampus. Representative immunoblots of hippocampal GluR1 (a), GluR2 (b), GluR3 (c), and GluR4 (d) from OLE or ARA mice after NaCl or Aβ42 injections are shown. Densitometric analyses were performed to determine signal intensities normalized to β-tubulin. Data are expressed as the percentage of control OLE mice injected with NaCl (* p < 0.05 comparing the four groups of mice). Results are shown as mean ± SEM of immunoblots performed for all animals (OLE groups n = 4, ARA groups n = 6). (PPTX 253 kb

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

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. Keywords Alzheimer's disease; Cytosolic phospholipase A2; Soluble beta-amyloid oligomers; Memory; Apoptosis; Synaptotoxicity; Amyloid precursor protei