Modulation of amyloid-β-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid

The age-related deficit in long-term potentiation (LTP) in the dentate gyrus is positively correlated with hippocampal concentration of the pro-inflammatory cytokine, interleukin-1 beta (IL-1 beta). Previous evidence also indicates that the inhibition of LTP induced by intracerebroventricular injection of amyloid-beta(1-40) (A beta) is accompanied by increased hippocampal IL-1 beta concentration and IL-1 beta-stimulated signalling, specifically activation of the stress-activated protein kinase, c-jun N-terminal kinase (JNK). We considered that the underlying age-related neuroinflammation may render older rats more susceptible to A beta administration and, to investigate this, young, middle-aged and aged rats were injected intracerebroventricularly with A beta or vehicle. Hippocampal IL-1 beta concentration, JNK phosphorylation, expression of the putative A beta receptor, Receptor for advanced glycation end products (RAGE) and the microglial cell surface marker, CD40 were assessed. We report that A beta inhibited LTP in a concentration-dependent manner in young rats and that this was accompanied by concentration-dependent increases in hippocampal IL-1 beta and expression of phosphorylated JNK, RAGE and CD40. While 20 mu mol/L A beta exerted no significant effect on LTP in young rats, it inhibited LTP in middle-aged and aged rats and the increased vulnerability of aged rats was associated with increased IL-1 beta concentration. Treatment of rats with eicosapentaenoic acid attenuated the inhibitory effect of 60 mu mol/L A beta on LTP in young rats and the effect of 20 mu mol/L A beta in middle-aged and aged rats. We present evidence which indicates that the effect of eicosapentaenoic acid may be linked with its ability to stimulate activation of peroxisome proliferator-activated receptor gamma.