How does 11beta-hydroxysteroid dehydrogenase type 1 deficiency protect against age-related cognitive impairments ?

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Memory loss with advancing age is a common and distressing problem. Over-exposure to stress, and in particular to the glucocorticoid (steroid) hormones such as cortisol that are released by stress, can, with time, cause memory impairments. The eldely are especially vulnerable to this. We discovered an enzyme that amplifies cortisol levels locally in the brain. Mice lacking this enzyme resist the expected memory-impairments with ageing. To see if this matters in humans we performed two small trials which suggested that in healthy elderly men or subjects with type 2 diabetes treatment for a few weeks with an inhibitor of the enzyme also produced improvements in memory. In the present study we are going to determine how the enzyme acts in the mouse brain to affect learning and memory. We will sort out whether it really acts to alter steroid levels in brain tissue, how this responds to long-term stress and if ageing makes this system more or less susceptible to treatment.This study will add crucial evidence to an exciting new avenue to possible treatments for a major unmet medical need.