11beta-hydroxysteroid dehydrogenase type 1 expression is increased in the aged mouse hippocampus and parietal cortex and causes memory impairments

Abstract

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.

Figure 1.

Cognitively impaired aged mice have increased 11β-HSD1 mRNA in hippocampus and cortex. a, Aged 24–27 month C57BL/6J mice (n = 14) show impaired spatial learning in the water maze [escape latency and path length (mean ± SEM) to find submerged platform]; *p < 0.001, compared with young 6 m controls (n = 10). b, Aged mice have increased 11β-HSD1 mRNA in CA3 hippocampal and cortical layer V cells; *p < 0.05 compared with young. c, 11β-HSD1 mRNA expression in CA3 hippocampus and layer V cortex correlates (p < 0.05), with mean path length (day 5) to find the hidden platform.

Figure 2.

Forebrain overexpression of 11β-HSD1 causes cognitive decline with aging. a, Left, Immunohistochemical localization of CamIIK-HSD1 transgene using HA-tag antibodies in cerebral cortex (A), hippocampus (B), amygdala (C), and lateral septum (D). Right, 11β-HSD1 activity (percentage conversion corticosterone-11-dehydrocorticosterone) was increased (*p < 0.05) in cerebral cortex and hippocampus of CamIIK-HSD1 (Tg) mice compared with wt, n = 7 per group. b, Aging (18 months), but not young (6–9 months) (n = 8/group), Tg mice display delayed learning of water maze task compared with age-matched wt littermates; *p < 0.05, compared with respective day 1 value. c, Attenuated retention of conditioned behavior in aging Tg mice. Young and aging Tg and wt mice were tested for latency to move from light to dark compartments on day 2 shock trial (D2.1) and 5 h postshock (D2.2); *p < 0.05 compared with D2.1 value.