Lack of tissue glucocorticoid reactivation in 11beta -hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments.
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) intracellularly regenerates active corticosterone from circulating inert 11-dehydrocorticosterone (11-DHC) in specific tissues. The hippocampus is a brain structure particularly vulnerable to glucocorticoid neurotoxicity with aging. In intact hippocampal cells in culture, 11beta-HSD-1 acts as a functional 11beta-reductase reactivating inert 11-DHC to corticosterone, thereby potentiating kainate neurotoxicity. We examined the functional significance of 11beta-HSD-1 in the central nervous system by using knockout mice. Aged wild-type mice developed elevated plasma corticosterone levels that correlated with learning deficits in the watermaze. In contrast, despite elevated plasma corticosterone levels throughout life, this glucocorticoid-associated learning deficit was ameliorated in aged 11beta-HSD-1 knockout mice, implicating lower intraneuronal corticosterone levels through lack of 11-DHC reactivation. Indeed, aged knockout mice showed significantly lower hippocampal tissue corticosterone levels than wild-type controls. These findings demonstrate that tissue corticosterone levels do not merely reflect plasma levels and appear to play a more important role in hippocampal functions than circulating blood levels. The data emphasize the crucial importance of local enzymes in determining intracellular glucocorticoid activity. Selective 11beta-HSD-1 inhibitors may protect against hippocampal function decline with age.
Center for the Study of the Aging Brain, Molecular Medicine Center, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. Joyce.Yau@ed.ac.uk
J L
JL
Yau
J
J
Noble
C J
CJ
Kenyon
C
C
Hibberd
Y
Y
Kotelevtsev
J J
JJ
Mullins
J R
JR
Seckl
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000375:Aging / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003345:Corticosterone / Q000097:blood*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007859:Learning Disabilities / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014156:Transcortin / Q000378:metabolism
D001786:Blood Glucose; D014156:Transcortin; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D003345:Corticosterone