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

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Molecular Medicine

Abstract

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.

Technical Summary

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.

Publications


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Holmes MC (2010) 11beta-hydroxysteroid dehydrogenase type 1 expression is increased in the aged mouse hippocampus and parietal cortex and causes memory impairments. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Sooy K (2010) Partial deficiency or short-term inhibition of 11beta-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice. in The Journal of neuroscience : the official journal of the Society for Neuroscience









 
Description 2011 press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The University of Edinburgh issued a press release on the Yau et al, 2011 Journal of Neuroscience publication. The results of this activity sparked good media coverage (examples listed below).
Journal of Neuroscience paper on link between stress and memory loss
6/04/11: (Medindia) (Plus News Pakistan (Pakistan)) (United Press International) (India Pharma News) (Indian Express (India)) (Asian News International) (XINCCN (China)) (The Evening Chronicle) (Metro) (The Herald) (The Press and Journal) (Yorkshire Post) (The Manchester Evening News) (The Edinburgh Evening News) (The Sun) (The Daily Express) (The Daily Mail) (BBC online) (Telegraph and Argus) (BBC Regional Radio - Other UK) (West Sound (Radio)) (Forth 2 (Radio)) (BBC Regional Radio - Other UK) (Forth One (Radio)) (Joyce Yau) (The Star) (The Daily Record)

Journalists from the local radio station (Radio Forth) asked for an interview with J. Yau, part of which was included in the morning radio news. There were also telephone enquiries including from SAGA who wanted to know more about the research and what it means. In addition to the general press, it was also covered in various websites e.g.
www.worldhealth.net/news/new-discoveries-aging-related-memory-loss/
www.myscience.cc/en/wire/study_sheds_light_on_memory_loss-2011-edinburgh
www.physorg.com/news/2011-04-older-age-memory-loss-tied.html
www.parentgiving.com/elder-care/newsflash/stress-memory-loss-culprit-in-aging/
Year(s) Of Engagement Activity 2011
URL http://www.ed.ac.uk/news/all-news/memory-060411
 
Description Alzheimer's Research UK public talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Members of the public attended three short talks lasting 1 hour in total on Alzheimer's, dementia, current treatments and latest research at the university of Edinburgh. JY's talk on Stress and Dementia which included research data funded by MRC grant G0501596, generated questions and discussion afterwards. Some audience members stayed behind for informal chats with the speakers over tea and coffee.

No notable impact as yet.
Year(s) Of Engagement Activity 2013
 
Description University of Edinburgh Let's talk about Health public lecture series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The public lecture (Delirium and Dementia in old age: do our stress hormones contribute?) which consisted of 2 interconnected talks generated a lot of interest. The intended purpose of the lecture was to disseminate new research within the University that is increasing our understanding of diseases and providing new advances in treatment. On the night, approx 160 members of the public, including school children attended. The lecture generated many questions and discussions. Feedback from the audience was very good (e.g. "A very informative talk on the whole"; "Very pleased to see such an attendance of younger people"; "enjoyed mouse experiment results"; "Lots of interesting info!'; "Great slides!"; "Great job! Really enjoyed the talks"; "Very professional excellent presentations").
Year(s) Of Engagement Activity 2016
URL http://www.ed.ac.uk/news/2015/healthtalks
 
Description Wellcome Trust Masterclass in Clinical Neuroscience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Wellcome Trust Masterclass in Clinical Neuroscience: Tackling Cognitive Dysfunction in mood disorders: Focus on monoamines and corticosteroids (organizer Dr Richard McQuade) Matfen Hall, Northumberland, UK (5th - 7th March 2008)
Title of JY's talk: "11-ß-HSD manipulation and cognition."
This small gathering of 50 participants (mostly from UK and Europe) generated many questions and discussions.

no notable impact
Year(s) Of Engagement Activity 2008
URL http://research.ncl.ac.uk/cadence/2008-masterclass.htm