Role of glucocorticoid receptors on dendritic spine plasticity in an Alzheimer’s disease animal model

AIMS: Glucocorticoids hormones regulate stress response and are implicated in numerous diseases. The aim of our research is to assess the role of glucocorticoids in the pathogenesis of Alzheimer’s Disease (AD) and, in particular, to evaluate how the administration of agonists and antagonist of glucocorticoid receptors (GR) alter synaptic plasticity, causing a remodeling of dendritic spines in an AD mouse model (3xTg). METHOD: We administered either dexamethasone, an agonist of GR, or mifepristone, an antagonist of GR, to 6 month old 3xTg male mice. After perfusion with paraformaldehyde, brains were processed for Golgi Cox staining to highlight dendritic spines in a subset of neurons. We acquired images, reconstructed dendrites and, finally, calculated the dendritic spine density using the Imaris software (Bitplane). RESULTS: We found that dexamethasone causes a 23% reduction of spine density in CA1 region of hippocampus, whereas mifepristone resulted in a 14% significant increase, together with a modification of spine morphology. CONCLUSION: Dexamethasone-dependent reduction of spines is bigger than the one found in literature for treated wild type mice, suggesting a synergy between the molecular pathways leading to AD and the molecular action of glucocorticoids. Considering mifepristone treatment results, the blocking of GR could represent a possible therapeutic approach to slow down the progression of AD. In further studies, we will perform the experiments with dexamethasone and mifepristone to 10-11 months old 3xTg male mice to evaluate their effects on brains also in the late phase of pathology and we will investigate the molecular mechanism underlying the dendritic spine density changes.