Chronic exposure to high dose of glucocorticoids (GC) is a key risk factor for the development of Alzheimer\u2019s Disease (AD), as recently described by clinical and genetic studies. Furthermore, hyper-activation of glucocorticoids receptors (GR) induces, in brain, alterations comparable to those produced by AD. In a transgenic mice model for AD, GC induces the increasing production of A\u3b240, A\u3b242 and Tau total, the most important and typical hallmarks of this dementia. Two of the key roles of GC in brain are the regulation of dendritic spine turnover and the inflammation state, two phenomena strongly altered in AD. The aim of my project was to investigate the correlation between glucocorticoids and Alzheimer\u2019s Disease. In particular, I focused my attention on how dendritic spine plasticity and microglia activation in CA1 region of hippocampus of 3xTg-AD mice are modified by modulation of glucocorticoid receptor with agonist and antagonist. Using an innovative combined Golgi Cox and immunofluorescence technique, we found that 5 days of treatment with 8mg/kg of dexamethasone, an agonist of GR, was able to vigorously reduce dendritic spine density in CA1 region of 3xTg-AD mice, both at 6 and 10 months of age and induced proliferation and activation of microglia. The activation of microglia could contribute to spine damage. On the contrary, the treatment with 20mg/kg of mifepristone, an antagonist of GR, strongly enhanced dendritic spine density in CA1 region, at both ages, results confirmed also by electron microscopy analyses. Moreover, the antagonist was able to improve the 3xTg-AD mice performance in Y-maze task at 10 months of ages and the proliferation of microglia, but it was not able to reduce the activation of microglia. I speculated that these apparently ambiguous results could be explained by the well-known biphasic behavior of GC in brain, as already observed for spine plasticity and memory. Additionally, in vitro experiments, using immunofluorescence and immunoblotting techniques, revealed that dexamethasone, clearly, induced activation of microglia in vitro, a result never described before. On the contrary, mifepristone promoted both activation and inhibition of microglia inflammatory state, suggesting the existence of a biphasic behavior of GC also on inflammation regulation. In conclusion, my data demonstrates that stress induced by dexamethasone exacerbate AD and promote a more rapid progression of the pathology through a premature reduction of dendritic spine density and enhancement of inflammation. Consequently, the use of antagonist, like mifepristone, could represent a promising therapeutic strategy to delay the onset and slow down the progression of AD. Taking in account the biphasic behavior of GC, the right dose and time of treatment need to be found, in order to obtain the best improvement: the increasing of spine turnover together with the reduction of inflammation and improvement of behavioral performances
