11beta-hydroxysteroid dehydrogenase type 1 expression is increased in the aged mouse hippocampus and parietal cortex and causes memory impairments.
Increased neuronal glucocorticoid exposure may underlie interindividual variation in cognitive function with aging in rodents and humans. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the regeneration of active glucocorticoids within cells (in brain and other tissues), thus amplifying steroid action. We examined whether 11beta-HSD1 plays a role in the pathogenesis of cognitive deficits associated with aging in male C57BL/6J mice. We show that 11beta-HSD1 levels increase with age in CA3 hippocampus and parietal cortex, correlating with impaired cognitive performance in the water maze. In contrast, neither circulating corticosterone levels nor tissue corticosteroid receptor expression correlates with cognition. 11beta-HSD1 elevation appears causal, since aging (18 months) male transgenic mice with forebrain-specific 11beta-HSD1 overexpression ( approximately 50% in hippocampus) exhibit premature age-associated cognitive decline in the absence of altered circulating glucocorticoid levels or other behavioral (affective) deficits. Thus, excess 11beta-HSD1 in forebrain is a cause of as well as a therapeutic target in memory impairments with aging.
Holmes
Megan C
MC
Endocrinology Unit, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
Carter
Roderick N
RN
Noble
June
J
Chitnis
Shruti
S
Dutia
Amy
A
Paterson
Janice M
JM
Mullins
John J
JJ
Seckl
Jonathan R
JR
Yau
Joyce L W
JL
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics* / Q000378:metabolism; D000367:Age Factors; D000375:Aging; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010296:Parietal Lobe / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2