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© 2015 by the Endocrine Society. 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-hydroxysteroiddehydrogenase type 1 (11β-HSD1) amplifies intracellularglucocorticoid 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 intracerebroventriculardrug administration to the central nervous system alone. In theTg2576 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.
Author(s): Sooy K, Noble J, McBride A, Binnie M, Yau JLW, Seckl JR, Walker BR, Webster SP
Publication type: Article
Publication status: Published
Journal: Endocrinology
Year: 2015
Volume: 156
Issue: 12
Pages: 4592-4603
Print publication date: 01/12/2015
Online publication date: 01/12/2015
Acceptance date: 19/08/2015
ISSN (print): 0013-7227
ISSN (electronic): 1945-7170
Publisher: Endocrine Society
URL: https://doi.org/10.1210/en.2015-1395
DOI: 10.1210/en.2015-1395
PubMed id: 26305888
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