Modulation of dendritic spine plasticity, neuroinflammation and neurogenesis in 3XTG-AD mice hippocampus through glucocorticoid receptors

AIMS: The Glucocorticoids hormones act, through mineralcorticoid and glucocorticoid receptors (GRs). GRs are activated by high concentrations of glucocorticoids that in brain induced alteration comparable to those produced by Alzheimer’s Disease (AD). The aim is to assess the role of GRs in the pathogenesis of AD, related to synaptic plasticity, microglia activation and neurogenesis, in 3xTg-AD mouse model. METHOD: We administered agonist (dexamethasone) or antagonist (mifepristone) of GRs, to 3xTg male mice. Brains were processed for Golgi Cox staining to highlight dendritic spines and/or in combination with immunofluorescence using antibody of IBA1, for microglia. We also treated cultures of cortical and hippocampal neurons from E18 pups of 3xTg and C57BL/6 mice, and cultures of microglia from C57BL/6. RESULTS: Dexamethasone induced, on neurons, a 23% and 14% reduction of spine density in CA1 region of hippocampus, respectively at 6 and 10 months of age, whereas mifepristone resulted in a 14% and 10.5% significant increase. Related to microglia, dexamethasone induced in CA1 an increase of density (by 30%), IBA1 signal and hypertrophy. CD68 signal, a marker of phagocytosis, is increased in microglia cultures after dexamethasone treatment and reduced after mifepristone treatment. In neuron cultures, Tau and GR are clearly detectable and increased in 3xTg rather than C57BL/6. We are also treating them with glucocorticoids to underline spine changes, using PSD95, and the involvement of Rho GTPases, N-cadherin and BDNF pathways. Moreover, we are treating animals with BrdU to investigate hippocampal neurogenesis. CONCLUSION: There could be a synergy between the molecular pathways existing in AD and the molecular action of glucocorticoids. GR hyper-activation, in 3xTg mice, induces a degeneration of dendritic spines in CA1 region of hippocampus, through neuron intracellular mechanisms and microglia activation. So, blockade of GR could represent a therapeutic target to slow down the AD progression.