Endocrine Abstracts

Chronic stress or excess glucocorticoids may promote brain ageing and cognitive decline. Elevated blood cortisol levels or increased sensitivity to cortisol’s action in brain cells play a crucial role in the development of age-dependent memory deficits. It is now recognized that the concentration of glucocorticoids within specific tissues including brain are derived not just from blood hormone levels but also from the local regeneration of active glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Our studies highlight the important contribution of brain 11β-HSD1 generated glucocorticoids in age-associated memory decline. Thus life-long deficiency of 11β-HSD1 or short-term 11β-HSD1 inhibition protects against spatial memory impairments in aged mice, despite elevated plasma glucocorticoid levels. We recently investigated whether brain 11β-HSD1 generated glucocorticoids also play a prominent role in stress-induced memory impairments. Here we present data that show chronic stress in mid-aged wild type mice leads to impaired spatial memory, an effect that persisted for at least 6 months after the period of stress thus accelerating cognitive ageing. Importantly, 11β-HSD1 deficient mice resisted both the immediate and persisting effects of chronic stress on impairment of spatial memory. 11β-HSD1 is therefore a promising novel target for the treatment of age and stress related cognitive impairments in humans.