Molecular and biophysical features of hippocampal “lipid rafts aging” are modified by dietary n‐3 long‐chain polyunsaturated fatty acids

“Lipid raft aging” in nerve cells represents an early event in the development of aging‐related neurodegenerative diseases, such as Alzheimer's disease. Lipid rafts are key elements in synaptic plasticity, and their modification with aging alters interactions and distribution of signaling molecules, such as glutamate receptors and ion channels involved in memory formation, eventually leading to cognitive decline. In the present study, we have analyzed, in vivo, the effects of dietary supplementation of n‐3 LCPUFA on the lipid structure, membrane microviscosity, domain organization, and partitioning of ionotropic and metabotropic glutamate receptors in hippocampal lipid raffs in female mice. The results revealed several lipid signatures of “lipid rafts aging” in old mice fed control diets, consisting in depletion of n‐3 LCPUFA, membrane unsaturation, along with increased levels of saturates, plasmalogens, and sterol esters, as well as altered lipid relevant indexes. These changes were paralleled by increased microviscosity and changes in the raft/non‐raft (R/NR) distribution of AMPA‐R and mGluR5. Administration of the n‐3 LCPUFA diet caused the partial reversion of fatty acid alterations found in aged mice and returned membrane microviscosity to values found in young animals. Paralleling these findings, lipid rafts accumulated mGluR5, NMDA‐R, and ASIC2, and increased their R/NR proportions, which collectively indicate changes in synaptic plasticity. Unexpectedly, this diet also modified the lipidome and dimension of lipid rafts, as well as the domain redistribution of glutamate receptors and acid‐sensing ion channels involved in hippocampal synaptic plasticity, likely modulating functionality of lipid rafts in memory formation and reluctance to age‐associated cognitive decline. “Lipid rafts aging” has been described as a phenomenon associated with nerve cell membranes during normal brain aging, which is exacerbated in pathological processes leading to neurodegeneration. Dietary n‐3 long‐chain polyunsaturated fatty acids (n‐3 LCPUFA) partly revert the molecular and biophysical alterations of hippocampal lipid rafts associated with aging. Besides membrane lipidome and microviscosity, the diet also modified lipid rafts dimensions and the membrane distribution of glutamate receptors and acid‐sensing ion channels involved n hippocampal synaptic plasticity.