Open AccessGlucose deprivation increases tau phosphorylation via P 38 mitogen‐activated protein kinase
Author(s) -
Lauretti Elisabetta,
Praticò Domenico
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12381
Subject(s) - phosphorylation , kinase , p38 mitogen activated protein kinases , biology , protein kinase a , microbiology and biotechnology , mitogen activated protein kinase , signal transduction , tau protein , biochemistry , medicine , alzheimer's disease , disease
Summary Alterations of glucose metabolism have been observed in Alzheimer's disease ( AD ) brain. Previous studies showed that glucose deprivation increases amyloidogenesis via a BACE ‐1‐dependent mechanism. However, no data are available on the effect that this condition may have on tau phosphorylation. In this study, we exposed neuronal cells to a glucose‐free medium and investigated the effect on tau phosphorylation. Compared with controls, cells incubated in the absence of glucose had a significant increase in tau phosphorylation at epitopes Ser202/Thr205 and Ser404, which was associated with a selective activation of the P38 mitogen‐activated protein kinase. Pharmacological inhibition of this kinase prevented the increase in tau phosphorylation, while fluorescence studies revealed its co‐localization with phosphorylated tau. The activation of P38 was secondary to the action of the apoptosis signal‐regulating kinase 1, as its down‐regulation prevented it. Finally, glucose deprivation induced cell apoptosis, which was associated with a significant increase in both caspase 3 and caspase 12 active forms. Taken together, our studies reveal a new mechanism whereby glucose deprivation can modulate AD pathogenesis by influencing tau phosphorylation and suggest that this pathway may be a new therapeutic target for AD .