Abstract
Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia.
Highlights
Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer’s disease
It has been postulated that excess glucocorticoids increase levels of amyloid precursor protein (APP) and APP cleaving enzyme (-site APP-cleaving enzyme [BACE]), leading to increased amyloid A (A) formation, reduced A degradation via attenuation of insulin degrading enzyme (IDE), and increased -expression [10]
To show that the effects of UE2316 were not merely due to any peripheral metabolic actions of 11-HSD1 inhibition, the agent was administered intracerebroventricularly to aged male C57BL/6 mice (24 mo, obtained from an in-house stock) were treated with either vehicle (n ϭ 9) or 100 ng/h UE2316 in artificial cerebrospinal fluid (CSF) (n ϭ 8) administered via intracerebroventricular infusion, for 9 days, as previously described [23]
Summary
Cognitive and Disease-Modifying Effects of 11-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer’s Disease. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced A plaque pathology and that 11-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer’s dementia. Whereas 11-HSD1 inhibition improves glucose homeostasis and other metabolic parameters in obesity, metabolic changes were not correlated with cognitive effects in aged rodents or humans. These results support examination of selective 11-HSD1 inhibitors in the treatment of age-related cognitive impairments. We generated and used UE2316, a novel and selective inhibitor of both human and rodent 11-HSD1 with a low nanomolar IC50 value and high penetration into the brain [19, 20]
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