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P3‐033: Involvement of endoplasmic reticulum stress in tauopathy
Author(s) -
Sakagami Yukako,
Kudo Takashi,
Mitsuda Teruhiko,
Tanimukai Hitoshi,
Okochi Masayasu,
Imaizumi Kazunori,
Takeda Masatoshi
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1251
Subject(s) - endoplasmic reticulum , unfolded protein response , tauopathy , tau protein , microbiology and biotechnology , tunicamycin , sh sy5y , messenger rna , transfection , untranslated region , biology , chemistry , cell culture , neurodegeneration , alzheimer's disease , medicine , gene , biochemistry , neuroblastoma , genetics , disease
(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.