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

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.

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) intracellularly regenerates active glucocorticoids from circulating inert forms thus amplifying levels within specific tissues. Aged 11beta-HSD1-/- mice show amelioration of glucocorticoid-associated learning impairments found in age-matched controls despite similarly elevated plasma corticosterone levels, normally expected to impair memory if considered on its own. Local metabolism of glucocorticoids is thus a major factor determining steroid effects on hippocampal function. This application will dissect how 11beta-HSD1 regulates cognitive function with ageing. Specifically we wish to answer; (i) is the protected cognitive phenotype in aged 11beta-HSD1-/- mice the consequence of lowered hippocampal corticosterone levels in adulthood or of ?developmental? effects? (ii) can central inhibition of 11beta-HSD1 enhance memory in already cognitively impaired aged mice? (iii) how do hippocampal tissue corticosterone levels vary during a spatial learning task in the absence and presence of 11beta-HSD1? and (iv) are 11beta-HSD1-/- effects dependent on altered hippocampal mineralocorticoid and/or glucocorticoid receptor occupancy? To investigate these questions we will use a broad range of techniques including stereotaxic surgery to administer inhibitors or corticosterone centrally, behavioural testing in the watermaze and Y-maze, state-of-the-art brain in vivo microdialysis in freely moving mice, radioimmunoassays for corticosterone, and in situ hybrization histochemistry. Data derived will provide fundamental mechanistic information about a major theory of variation in cognitive ageing and will dissect a novel therapeutic approach.