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

Abstract

SummaryAlterations 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.

Efficacy of Cilostazol Administration in Alzheimer's Disease Patients with White Matter Lesions: A Positron-Emission Tomography Study

“…Hypoperfusion and oxygen-glucose deprivation also induced both necrotic and apoptotic cell death of astrocytes by tau phosphorylation [37]. Glucose deprivation increases tau phosphorylation via P38 mitogen-activated protein kinase, and then finally, glucose deprivation induces cell apoptosis by tau phosphorylation [38]. Therefore, cilostazol may prevent or attenuate tauopathy-related cell apoptosis with positive effects of increased glucose uptake by cilostazol.…”

Hippocampal metabotropic glutamate receptor long‐term depression in health and disease: focus on mitogen‐activated protein kinase pathways

“…). The over‐activation of this pathway is significant as p38 activation has been shown to play a role in the hyperphosporylation of tau, which results in neurofibrillary tangles, a hall mark of Alzheimer's (Lauretti and Praticò ). Preventing the up‐regulation of MAPK pathways could be a therapeutic strategy to delay the cognitive impairments observed in AD.…”

“…This could be because the inhibition of p38 prevents the increased endocytosis of AMPARs on exposure of endogenous Ab and therefore rescues the impairment of LTP (Wang et al 2004;Nomura et al 2012). The over-activation of this pathway is significant as p38 activation has been shown to play a role in the hyperphosporylation of tau, which results in neurofibrillary tangles, a hall mark of Alzheimer's (Lauretti and Pratic o 2015). Preventing the up-regulation of MAPK pathways could be a therapeutic strategy to delay the cognitive impairments observed in AD.…”

Kinetic and thermodynamic study of beta-Boswellic acid interaction with Tau protein investigated by surface plasmon resonance and molecular modeling methods

“…17 Diabetes and insulin resistance are strong risk factors for cognitive decline and AD. 18,19 The effect of glucose on tau aggregation both via interfering in Tau phosphorylation, 20 Tau cleavage and Tau glycation 17,21 have been considered as probable mechanisms in crosstalk between AD and diabetes. 21 In addition, the effect of BBA on Tau stability and the secondary structure was studied by the application of CD measurements.…”