Partial deficiency or short-term inhibition of 11beta-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoids (GCs) from intrinsically inert 11-keto substrates inside cells, including neurons, thus amplifying steroid action. Excess GC action exerts deleterious effects on the hippocampus and causes impaired spatial memory, a key feature of age-related cognitive dysfunction. Mice with complete deficiency of 11β-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11β-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11β-HSD1 knock-out mice, with ∼60% reduction in hippocampal 11β-reductase activity throughout life, were protected against spatial memory impairments in the Y-maze compared to age-matched congenic C57BL/6J controls. Pharmacological treatment of aged C57BL/6J mice with a selective 11β-HSD1 inhibitor (UE1961) for 10 d improved spatial memory performance in the Y-maze (59% greater time in novel arm than vehicle control). These data support the use of selective 11β-HSD1 inhibitors in the treatment of age-related cognitive impairments.

Figure 1.

Maintained spatial memory in the Y-maze for aged 11β-HSD1^+/− and 11β-HSD1^−/− mice but not aged C57BL/6J controls. A, Both young (6 months young; n = 6–8/genotype) and aged (24 months aged; n = 7–8/genotype) mice of C57BL/6J (CON) controls, 11β-HSD1^+/− (KO+/−), and 11β-HSD1^−/− (KO−/−) mice were able to perform the immediate version of the Y-maze with the 1 min ITI. B, Young mice of all three genotypes show intact spatial memory (with 2 h ITI) spending more time in the novel arm than the other two arms. Aged C57BL/6J (but not aged 11β-HSD1^+/− and aged 11β-HSD1^−/−) mice show impaired spatial memory with 2 h ITI. Values are means ± SEM. *p < 0.05 compared to novel arm. ^§ p < 0.01 compared to novel arm of aged C57BL/6J mice.

Figure 2.

11β-Reductase activity is reduced in brain of aged 11β-HSD1^+/− mice. The 11β-reductase activity was measured in tissue homogenates of the aged mice [C57BL/6J (CON) controls, 11β-HSD1^+/− (KO+/−), and 11β-HSD1^−/− (KO−/−), n = 7–8/genotype] incubated with [³H]-11-dehydrocorticosterone (11-DHC), and the percentage conversion to active [³H]-corticosterone (CORT) was measured. Enzyme activity levels in the tissues of aged 11β-HSD1^−/− mice were not detectable. Values are means ± SEM. *p < 0.001 compared to C57BL/6J controls.

Figure 3.

Plasma corticosterone levels are increased with age but are not affected by lifelong 11β-HSD1 deficiency. Basal corticosterone (CORT) levels were measured from tail venesection blood samples taken in the morning 1 h after lights on from young (6 months old; n = 6–8/genotype) and aged (24 months old; n = 7–8/genotype) C57BL/6J (CON) controls, 11β-HSD1^+/− (KO+/−), and 11β-HSD1^−/− (KO−/−) mice. Values are means ± SEM. *p < 0.05 compared to corresponding young mice of same genotype.

Figure 4.

Treatment of aged C57BL/6J mice with a selective 11β-HSD1 inhibitor UE1961 decreases 11β-reductase activity in the hippocampus and improves spatial memory retention in the Y-maze. A, Chemical structure of UE1961. B, 11β-Reductase activity was measured in tissue homogenates of the aged mice following administration of 10 mg/kg UE1961 (inhibitor) incubated with [³H]-11-dehydrocorticosterone (11-DHC) and the percentage conversion to active [³H]-corticosterone (CORT) was measured. C, Spatial memory retention as measured in the Y-maze with a 2 h ITI was significantly better in the UE1961-treated mice than vehicle-treated controls (n = 9–10/group). Values are means ± SEM. *p < 0.05 compared to corresponding novel arm. ^§ p < 0.001 compared to novel arm of vehicle-treated controls.