Journal
NEUROBIOLOGY OF AGING
Volume 45, Issue -, Pages 109-122Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2016.05.018
Keywords
Alzheimer's disease; Glucocorticoid receptors; HPA axis; Amyloid-beta peptide; Hippocampus; Selective GR modulator; A beta(25-35) peptide; Rat
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Funding
- INSERM, University of Montpellier
- EPHE annual resources (France)
- Agence Nationale de la Recherche (ANR) under the program Investissements d'Avenir [ANR-11-LABX-0021-LipSTIC]
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In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuro-inflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-beta peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment. (C) 2016 Elsevier Inc. All rights reserved.
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