BACKGROUND:

Polyunsaturated 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.

METHODS:

Two 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.

RESULTS:

We 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.

CONCLUSIONS:

Dietary 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.

Polyunsaturated fatty acids play crucial role in neuronal functions and the modification of these compounds in 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 brain are poorly known.

In this work, two groups of 39 adult male Balb/C mice were fed respectively with an arachidonic or an oleic acid-enriched diet for 12 weeks. After 10 weeks of diet, mice received intracerebroventricular injections of either NaCl solutions or Aβ oligomers. Y-maze and Morris water maze tests were used to evaluate short- and long-term memory. At 12 weeks of diet mice were sacrificed and blood, liver and brain samples were collected for lipid and protein analyses.

Administration of the arachidonic acid-enriched diet induced short-term memory impairment and increased deleterious effects of amyloid-β oligomers on learning abilities. These cognitive alterations were associated to modifications of expression of AMPA receptors, PSD95 and GFAP in mouse cortex or hippocampus by arachidonic acid-enriched diet and Aβ oligomer administration. This diet also led to an unbalance between the main ω?6 fatty acids and the ω-3 fatty acids in favor of the first one in erythrocytes and liver as well as in the brain structures hippocampus and cortex. In the cortex, the dietary arachidonic acid induced also an increase of arachidonic acid-containing phospholipid species in phosphatidylserine class while intracerebroventricular injections modified several arachidonic and docosahexaenoic acids-containing species in the 4 phospholipid classes. Finally, we observed that dietary arachidonic acid decreased the expression of the neuronal form of acyl-coA synthetase 4 in the hippocampus and increased the cytosolic phospholipase A2 activation level in the cortex of our mice.

We concluded that dietary arachidonic acid could amplify Aβ oligomers neurotoxicity. Its consumption could constitute a risk factor of Alzheimer’s disease in humans and should be taken into account in the future preventive strategies. Its deleterious effect on the cognitive capacities could be linked to the balance between the arachidonic acid-mobilizing enzymes.