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Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer's disease

Lookup NU author(s): Professor Brian Walker

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Abstract

© 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.


Publication metadata

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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