Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

Aging Cell

Elisabetta Lauretti¹ 

[1] Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA

关键词: Alzheimer's disease;    amyloid beta;    glucose deprivation;    mitogen‐activated protein kinase;    neuronal cells;    tau phosphorylation;   

DOI  :  10.1111/acel.12381

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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