Cognitive and Disease-Modifying Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer's Disease.

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.

• Authors: Karen Sooy, June Noble, Andrew McBride, Margaret Binnie, Joyce L W Yau, Jonathan R Seckl, Brian R Walker, Scott P Webster
• Journal: Endocrinology (Endocrinology) Vol. 156 Issue 12 Pg. 4592-603 (Dec 2015) ISSN: 1945-7170 [Electronic] United States
• PMID: 26305888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (4-(2-chlorophenyl-4-fluoro-1-piperidinyl)(5-(1H-pyrazol-4-yl)-3-thienyl)methanone
• APP protein, human
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Pyrazoles
• Thiophenes
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Insulysin

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors)
• Alzheimer Disease (genetics, metabolism)
• Amyloid beta-Peptides (drug effects)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Behavior, Animal (drug effects)
• Cerebral Cortex (drug effects, pathology)
• Cognition (drug effects)
• Disease Models, Animal
• Humans
• Insulysin (drug effects, metabolism)
• Maze Learning
• Memory (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Plaque, Amyloid (pathology)
• Pyrazoles (pharmacology)
• Thiophenes (pharmacology)