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.
Yau
J L
JL
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
Noble
J
J
Kenyon
C J
CJ
Hibberd
C
C
Kotelevtsev
Y
Y
Mullins
J J
JJ
Seckl
J R
JR
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