Among the several changes which accompany ageing is a compromise in synaptic function, one manifestation of which is an impairment in long-term potentiation (LTP). Several cellular and molecular changes occur in the aged brain which are likely to contribute to this impairment; it has been shown recently that there is evidence of tissue stress in the aged hippocampus and the evidence suggests that this may be a pivotal factor in causing the age-related impairment in LTP. Thus activities of the stress-activated protein kinases, c-jun N-terminal kinase (JNK) and p38 are significantly increased in the hippocampus of the aged, compared with the young, rat. The evidence suggests that these changes are a consequence of increased hippocampal concentration of the proinflammatory cytokine, interleukin-1β (IL-1β), coupled with increased expression of IL-1 receptor type I (IL-1RI) and increased activation of IL-1 receptor associated kinase (IRAK). The age-related increase in activation of JNK and p38, which lead to activation of the transcription factors, c-jun and nuclear factor κB (NFκB), respectively, ultimately induces cellular changes which suggest that apoptotic cell death occurs in the aged brain. Thus cytochrome c translocation, caspase-3 activation and cleavage of poly ADP ribose polymerase (PARP) are enhanced in hippocampal tissue prepared from aged, compared with young, rats; consistently TUNEL staining was also shown to be enhanced in acutely dissociated cell prepared from aged, compared with young, rats.

The key role of IL-1β and the signalling events induced by IL-1 receptor activation in stimulating activities of JNK and p38 and in inducing cell death has been underscored in recent studies; thus several manoeuvres which reduce the age-related increase in IL-1β concentration or IL-1β-induced signalling inhibit activation of JNK and p38 and resultant apoptotic changes. These manoeuvres include treatment of rats with the polyunsaturated fatty acid, eicosapentaneoic acid (EPA) or phosphatidyl serine-bearing liposomes, both of which block the age-related increase in IL-1β concentration. Both treatment schedules inhibit the age-related impairment in LTP. Increased activation of JNK and p38 in hippocampus of aged rats is coupled with decreased activation of extracellular signal-regulated protein kinase (ERK) and the transcription factor, cAMP response element-binding protein (CREB), and the combined importance of these age-related changes has been emphasized in recent studies. It has emerged that a proportion of aged rats sustain LTP; the evidence suggests that about 25 % of 22 month-old animals sustain LTP. In a recent study, hippocampal tissue was prepared from aged rats which did and did not sustain LTP. Analysis revealed that IL-1β concentration, JNK activation and JNK translocation to the nucleus were significantly enhanced in hippocampal tissue prepared from aged rats which did not sustain LTP, compared with aged rats which sustained LTP and young rats. The data indicated that there was an indirect correlation between activation of JNK and activation of ERK, such that ERK activation was significantly reduced in hippocampus of aged rats which failed to sustain LTP, compared with young rats and aged rats which sustained LTP. These data will be discussed in the light of other findings which indicate that decreased hippocampal concentrations of anti-inflammatory cytokines, IL-4 and IL-10, and downregulation of signalling events triggered by IL-10 and IL-4 receptor activation, together with upregulation of IL-1β and IL-1β-triggered signalling, combine to lead to the age-related impairment in LTP.

This work was funded by the Health Research Board (Ireland), Enterprise Ireland and the Higher Education Authority (Ireland).