INHIBITING GLUCOCORTICOID RECEPTOR DIMERIZATION BLOCKS EFFECTS OF ACUTE STRESS ON Aβ IN FEMALE MICE

Abstract

Results from both human and animal studies over the last decade have identified a clear increase in the rate of Alzheimer's disease (AD) in women. Sex differences in the prevalence or severity of many diseases are well recognized. A common underlying feature of disorders more prevalent in females is an association with stress, such as in anxiety and depression. Stress increases glucocorticoids (GC) in the brain, and the link between GCs and AD has been confirmed by several studies. We previously found that acute stress rapidly increases levels of Aβ in the mouse brain. GCs function through a nuclear GC receptor (GR) that acts as a dimer to facilitate transactivation or as a monomer to repress transcription (transrepression). The sex-related differences in transactivation versus transrepression remain unclear and the influence of either pathway on AD pathology has not been defined. Using microdialysis, Aβ levels in the interstitial fluid (ISF) of the hippocampus were measured in male and female APP/PS1 mice (3–4 months old). Samples were collected every hour for a baseline period, 3-hour restraint stress, and 12-hour post stress period. To evaluate the effects of blocking the transactivation arm of GR signaling through GR dimerization, we crossed APP/PS1 mice with the glucocorticoid receptor dimerization deficient mouse model (GRdim), to create GRdim APP mice. We also studied the effects of pharmacologically blocking GR dimerization using Compound A, administered via reverse microdialysis before restraint stress. We observed a significant difference between male and female mice in the percent increase in ISF Aβ during acute stress, with female mice having a much greater and sustained increase in ISF Aβ compared to males. ISF Aβ levels in female GRdim APP mice did not rise dramatically during acute stress, and stayed near baseline during the post stress period. Compound A completely blocked the increase in ISF Aβ induced by restraint stress in female mice. These results suggest that females are more sensitive to stress-induced increases in Aβ, and that acute stress increases Aβ in female mice through a GR dimerization dependent mechanism.