期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 41, 页码 13867-13872出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2783-10.2010
关键词
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资金
- Medical Research Council (MRC) [G0501596]
- Wellcome Trust [078269]
- Research Councils UK
- Biotechnology and Biological Sciences Research Council
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- MRC
- British Heart Foundation Centre of Research Excellence
- MRC [G0501596] Funding Source: UKRI
- Medical Research Council [G0501596, G0700704B] Funding Source: researchfish
11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-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 beta-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11 beta-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11 beta-HSD1 knock-out mice, with similar to 60% reduction in hippocampal 11 beta-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 beta-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 beta-HSD1 inhibitors in the treatment of age-related cognitive impairments.
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