Loss of the atypical inflammatory response in juvenile and aged rats

Abstract

Epidemiological evidence indicates that the severity of many human neuropathologies is often age-related, and this also appears true in rodent models of human disease. In this study, we examined the inflammatory response within the brain to the archetypal pro-inflammatory cytokines interleukin-1beta (IL-1beta) or tumour necrosis factor-alpha (TNF-alpha). We assessed how the cerebral vasculature changes with age and whether any structural alterations are associated with altered cytokine sensitivities. Six hours after equivalent microinjections of IL-1beta or TNF-alpha, 3-week-old juvenile and 18-month-old aged rats displayed increased leucocyte recruitment, blood-brain barrier (BBB) breakdown, and a loss of specificity in the populations of leucocytes recruited when compared with the restricted profile observed in 2-month-old young adult rat brain. The expression of the tight junction protein claudin-1 was absent in those vessels where neutrophils were being actively recruited. To determine whether changes in the structure of the BBB might be responsible for the increased susceptibility observed at either end of the age spectrum, we compared the number of claudin-1 positive vessels in the unchallenged brain to the total number of vessels. Virtually all vessels in the young adult brain express claudin-1, but a significant proportion of vessels are claudin-1 negative in the juvenile rat brain. In the aged rat brain, the overall number of vessels is markedly reduced, but the majority of these still appear to be claudin-1 positive. The pattern of claudin-1 expression together with the change in vessel density indicates that the properties of the BBB change with age, and, despite similarities, the underlying cause of the heightened inflammatory response in the juvenile and in the aged brain is likely to differ. Indeed, the spatial characteristics of the cytokine-induced BBB breakdown are different at either end of the age spectrum. These studies identify two periods within the lifespan of a rat where susceptibility to pro-inflammatory mediators is dramatically increased.