Abstract
Glucocorticoids (GCs) are steroid hormones secreted as the end-product of the neuroendocrine stress cascade. Both absence and elevated GC mediate neurotoxic responses, suggesting that a narrow window ranging from physiological to slightly high GC mediate protective responses. The beneficial effects of GC are attributed to the transactivation of regulatory proteins and inhibition mediated by glucocorticoid receptor (GR) interactions with other co-factors. The glucocorticoid induced leucine zipper (GILZ) is a gene strongly upregulated by GC and mediates many of the anti-inflammatory and anti-proliferative effects of GC. Although GILZ is constitutively expressed in many tissues including the brain, the expression has been shown to occur with varying dynamics suggesting that the local milieu modulates its expression with consequent effects on cellular responses. Here we investigated the expression profile of GILZ in lipopolysaccharide (LPS) mediated neuroinflammation model of Alzheimer’s disease (AD). Our data suggest that the GILZ expression is downregulated in neuroinflammation correlating inversely with the pro-inflammatory cytokines and innate immune responses.
Highlights
Increased plasma glucocorticoids (GCs) are features of both aging and Alzheimer’s disease (AD; Huang et al, 2009)
We observed that the mean area of Iba+ microglial (Figures 1B,I) and glial fibrillary acidic protein (GFAP)+ astrocytes staining (Figures 1D,I) was higher in specific regions of the hippocampus of mice subjected to LPS induced neuroinflammation as compared to that in vehicle treated mice (Figures 1A,C,I)
While the control group of mice exhibited increased glucocorticoid induced leucine zipper (GILZ) staining (Figures 1G,I), GILZ+ cells were fewer in dentate gyrus (DG) and CA1 region the hippocampus of mice subjected to LPS induced neuroinflammation (Figures 1H,I)
Summary
Increased plasma glucocorticoids (GCs) are features of both aging and Alzheimer’s disease (AD; Huang et al, 2009). Increased secretion of GC can occur in response to various stimuli such as low plasma levels of GC, psychological or physical stress. The elevated GC in general is suppressed by a negative feedback loop, mainly regulated by the hypothalamic pituitary adrenal axis (HPA; Abrahám et al, 2006; Vyas et al, 2016). Aging has been associated with a decreased sensitivity of the HPA axis to GC feedback, which in turn leads to prolonged elevated levels of plasma GC (Lupien et al, 1999). The profound anti-inflammatory effects of GC suggest a neuroprotective role, emerging evidence strongly implicate elevated GC in potentiating the pro-inflammatory responses and neuroinflammation in the central nervous system (CNS). Multiple mechanisms are suggested for the effects of high GC on brain including dysregulated HPA axis, alterations in glial functions as well as structural remodeling of neurons with synaptic loss
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