Glucocorticoids deeply affect spine plasticity and inflammation in an animal model of Alzheimer’s Disease

Aim High levels of glucocorticoids, through activation of glucocorticoid receptors (GR), induce in brain alterations comparable to those occurring in Alzheimer’s disease (AD). The aim of this project is to assess the effects of GR modulation in the pathogenesis of AD in 3xTg-AD mouse model. Methods To investigate the effects of glucocorticoids on spine plasticity and inflammation, GR agonist (dexamethasone) or antagonist (mifepristone), were administrated on 3xTg male mice and combined Golgi Cox staining and immunofluorescence were performed to assess dendritic spine density and microglia activation, respectively. Glucocorticoid direct effects on microglia were studied on mouse microglial primary culture. In vivo,spine turnover was investigated through two-photon laser microscopy, following to AAV-GFP neuronal infection. Instead, the functionality of newborn spines was investigated using electron microscopy. Finally, changes in anxiety and cognitive performance were monitored via open field and novel object recognition tests. Results Dexamethasone reduced spine density and induced microglia activation and proliferation in the CA1 region of the hippocampus, at both 6 and 10 months of age, whereas mifepristone treatment significantly increased spine density. CD68 signal, a marker of phagocytosis, changed in microglia cultures after glucocorticoid treatment, indicating a direct effect of glucocorticoids on microglia. In vivo experiment analyses are currently ongoing. Conclusion GR hyper-activation induces a degeneration of dendritic spines in the hippocampus CA1 region, through a neuron intracellular mechanisms and microglia activation. Blockade of GR could represent a therapeutic target to slow down AD. These data suggest a synergy between glucocorticoids and AD.