No abstract

In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11␤-Hydroxysteroid dehydrogenase type 1 (11␤-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11␤-HSD1, but not 11␤-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebocontrolled crossover studies, administration of the 11␤-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). Although carbenoxolone has been reported to enhance hepatic insulin sensitivity in short-term studies, there were no changes in glycemic control or serum lipid profile, nor was plasma cortisol altered. 11␤-HSD1 inhibition may be a new approach to prevent͞ameliorate cognitive decline.

11␤-hydroxysteroid dehydrogenase type 1 (11␤-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, 11␤-HSD-1 acts as a functional 11␤-reductase reactivating inert 11-DHC to corticosterone, thereby potentiating kainate neurotoxicity. We examined the functional significance of 11␤-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 11␤-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 11␤-HSD-1 inhibitors may protect against hippocampal function decline with age.

Glucocorticoid receptor (GR) gene expression is regulated in a complex tissue-specific manner, notably by early-life environmental events that program tissue GR levels. We have identified and characterized several new rat GR mRNAs. All encode a common protein, but differ in their 5'-leader sequences as a consequence of alternate splicing of, potentially, 11 different exon 1 sequences. Most are located in a 3-kb CpG island, upstream of exon 2, that exhibits substantial promoter activity in transfected cells. Ribonuclease (RNase) protection analysis demonstrated significant levels of six alternate exons 1 in vivo in rat, with differences between liver, hippocampus, and thymus reflecting tissue-specific differences in promoter activity. Two of the alternate exons 1 (exons 1(6) and 1(10)) were expressed in all tissues examined, together present in 77-87% of total GR mRNA. The remaining GR transcripts contained tissue-specific alternate first exons. Importantly, tissue-specific first exon usage was altered by perinatal environmental manipulations. Postnatal handling, which permanently increases GR in the hippocampus, causing attenuation of stress responses, selectively elevated GR mRNA containing the hippocampus-specific exon 1(7). Prenatal glucocorticoid exposure, which increases hepatic GR expression and produces adult hyperglycemia, decreased the proportion of hepatic GR mRNA containing the predominant exon 1(10), suggesting an increase in a minor exon 1 variant. Such tissue specificity of promoter usage allows differential GR regulation and programming.

Glucocorticoids are pivotal in the maintenance of memory and cognitive functions as well as other essential physiological processes including energy metabolism, stress responses, and cell proliferation. Normal aging in both rodents and humans is often characterized by elevated glucocorticoid levels that correlate with hippocampus-dependent memory impairments. 11␤-Hydroxysteroid dehydrogenase type 1 (11␤-HSD1) amplifies local intracellular ("intracrine") glucocorticoid action; in the brain it is highly expressed in the hippocampus. We investigated whether the impact of 11␤-HSD1 deficiency in knock-out mice (congenic on C57BL/6J strain) on cognitive function with aging reflects direct CNS or indirect effects of altered peripheral insulin-glucose metabolism. Spatial learning and memory was enhanced in 12 month "middle-aged" and 24 month "aged" 11␤-HSD1Ϫ/Ϫ mice compared with age-matched congenic controls. These effects were not caused by alterations in other cognitive (working memory in a spontaneous alternation task) or affective domains (anxiety-related behaviors), to changes in plasma corticosterone or glucose levels, or to altered age-related pathologies in 11␤-HSD1 ؊/؊ mice. Young 11␤-HSD1 ؊/؊ mice showed significantly increased newborn cell proliferation in the dentate gyrus, but this was not maintained into aging. Long-term potentiation was significantly enhanced in subfield CA1 of hippocampal slices from aged 11␤-HSD1 ؊/؊ mice. These data suggest that 11␤-HSD1 deficiency enhances synaptic potentiation in the aged hippocampus and this may underlie the better maintenance of learning and memory with aging, which occurs in the absence of increased neurogenesis.

Increased neuronal glucocorticoid exposure may underlie interindividual variation in cognitive function with aging in rodents and humans. 11␤-Hydroxysteroid dehydrogenase type 1 (11␤-HSD1) catalyzes the regeneration of active glucocorticoids within cells (in brain and other tissues), thus amplifying steroid action. We examined whether 11␤-HSD1 plays a role in the pathogenesis of cognitive deficits associated with aging in male C57BL/6J mice. We show that 11␤-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. 11␤-HSD1 elevation appears causal, since aging (18 months) male transgenic mice with forebrain-specific 11␤-HSD1 overexpression (ϳ50% in hippocampus) exhibit premature age-associated cognitive decline in the absence of altered circulating glucocorticoid levels or other behavioral (affective) deficits. Thus, excess 11␤-HSD1 in forebrain is a cause of as well as a therapeutic target in memory impairments with aging.

No abstract

11␤-Hydroxysteroid dehydrogenase type 1 (11␤-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 11␤-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11␤-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11␤-HSD1 knock-out mice, with ϳ60% reduction in hippocampal 11␤-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 11␤-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 11␤-HSD1 inhibitors in the treatment of age-related cognitive impairments.