P3‐033: Involvement of endoplasmic reticulum stress in tauopathy

(AD) pathogenesis, however, the mechanism remains to be fully elucidated. In the current work, we investigated the role of glucocortitcoids on the AD-like phenotype. Methods:We administered the glucocorticoid dexamethasone to Tg2576 mice for 4 weeks and then investigated its effect on memory, beta-amyloid and tau levels and metabolism. Results: At the end of the treatment period we observed that mice receiving dexamethasone had a significant impairment in the fear conditioning paradigm compared with controls. Dexamethasone-treated animals showed a significant increase in the amount of brain soluble Ab 1-40 levels, but no alteration in the steady state levels of its precursor protein, APP, or in the major protease enzymes involved in its metabolism (i.e., ADAM-10, BACE-1 or gsecretase complex). While total tau-protein levels were unaltered between the two groups, we found that dexamethasone significantly reduced tau phosphorylation at specific sites that were mediated by changes in glycogen synthase kinase-3 beta activity. Finally, we observed a direct correlation between memory impairments and tau phosphorylation levels. Conclusions:Our study highlights the significant role that glucocorticoids play in exacerbating AD-like cognitive impairments via alteration of tauprotein phosphorylation state.