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P3‐384: Disease modifying effects of mifepristone (RU‐486) in the 3xTg‐AD mouse model of Alzheimer's disease
Author(s) -
Vargas David Baglietto,
Green Kim N.,
Medeiros Rodrigo,
Martinez-Coria Hilda,
LaFerla Frank M.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1926
Subject(s) - mifepristone , glucocorticoid , corticosterone , antiglucocorticoid , endocrinology , medicine , glucocorticoid receptor , hippocampal formation , hippocampus , downregulation and upregulation , context (archaeology) , hormone , chemistry , biology , pregnancy , biochemistry , genetics , gene , paleontology
Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of individuals. Stress is an important etiological factor that contributes to the progression of aging and Alzheimer’s disease (AD). Stress and the hypothalamic-pituitary-adrenal (HPA) axis, which controls circulating glucocorticoid (GC) hormone levels, are intimately related. Excess GC secretion has been documented as an early feature of AD, implicated in the pathogenesis (neuronal atrophy, dysfunction, and memory impairments). We previously showed that excessive circulating GC upregulate both Ab and tau pathologies in the 3xTg-AD mouse model. Methods: The aim of the present study was to analyze the effect of the glucocorticoid antagonist RU-486 (mifepristone: 17b-hydroxy11a-(4-dimethylaminophenyl)-17a-(1-propynyl)-estra-4, 9dien-3-one; Innovative Research of America, Sarasota, FL) in the 3xTg-AD mice at an age where extensive hippocampal damage leads to upregulated circulating corticosterone levels. Mifepristone pellets (15 mg pellets and 60-day release at continuous flow of 10mg/h) were implanted intrascapularly in the 3xTg-AD at 12 months of age. Results: Mifepristone treatment reduced plasma corticosterone levels and brain GC receptor levels, compared to vehicle-implanted animals. Notably, treated mice showed an improvement in several cognitive tests (novel context, place, and object recognition; Morris water mice). These cognitive improvements were associated with a drastic reduction in both soluble and insoluble Ab levels as well as robust reductions in steady state levels of tau, including reduced somatodendritic accumulation within hippocampal neurons. Conclusions: Our findings demonstrate that anti-glucocorticoid strategies could be effective for the treatment of AD, and crucially show robust disease modifying effects in addition to preventing the effects of elevated circulating glucocorticoids.