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

随着年龄的增长，记忆丧失是一个普遍而令人痛苦的问题。过度暴露在压力下，特别是压力释放的糖皮质激素（类固醇）激素，如皮质醇，随着时间的推移，会导致记忆障碍。老年人尤其容易受到这种伤害。我们发现了一种酶可以在大脑中局部放大皮质醇水平。缺乏这种酶的老鼠抵抗了预期的随着年龄增长的记忆损伤。为了看看这是否对人类有影响，我们进行了两项小型试验，结果表明，在健康的老年人或患有2型糖尿病的受试者中，使用酶抑制剂治疗几周也能提高记忆力。在目前的研究中，我们将确定这种酶是如何在小鼠大脑中影响学习和记忆的。我们将弄清楚它是否真的能改变脑组织中的类固醇水平，它对长期压力的反应，以及衰老是否会使这个系统更容易受到治疗。这项研究将为一个令人兴奋的新途径提供关键证据，以可能治疗一个主要的未满足的医疗需求。

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.