Glucocorticoids, 11beta-HSD1 and cognitive function with ageing

Abstract

Cumulative exposure to high glucocorticoid levels is a major factor advanced to explain individual decline in cognitive function with ageing. Current manipulations to maintain low circulating glucocorticoid levels throughout life (adrenalectomy with low dose corticosterone replacement, neonatal handling), though effective in preventing the emergence of memory deficits with age in rodent models, are however not clinically applicable. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses the intracellular regeneration of active glucocorticoids from circulating inert 11-keto steroids thus amplifying glucocorticoid levels within specific target cells. In primary hippocampal neurons in vitro, inhibition of 11beta-HSD1 attenuates glucocorticoid-associated neurotoxicity. To determine the importance of 11beta-HSD1 in the ageing brain in vivo, we examined the impact of enzyme loss on hippocampal function using transgenic mice lacking expression of 11beta-HSD1. Wildtype mice develop elevated plasma corticosterone levels with age that correlated with hippocampal specific learning deficits in the watermaze. In contrast, despite similar elevated plasma corticosterone levels, aged 11beta-HSD1 knockout mice show significantly better learning than age-matched wildtype controls; this implicates lower intracellular corticosterone levels through the lack of 11-dehydrocorticosterone re-activation. Consistent with this, aged 11beta-HSD1 knockout mice show lower hippocampal tissue corticosterone levels than in wildtype controls. At the cellular level, enhanced hippocampal long-term potentiation in the CA1 region of aged 11beta-HSD1 knockout mice may, in part, underlie the improved cognitive function.