Hypoglycemia Induces Tau Hyperphosphorylation

Chu-Wan      Lee; Yao-Hsiang      Shih; Shih-Ying      Wu; Tingting      Yang; Chingju      Lin; Yu-Min      Kuo

Abstract

Cerebral hypoglycemia/hypometabolism is associated with Alzheimer’s disease (AD) and is routinely used to assist clinical diagnosis of AD by brain imaging. However, whether cerebral hypoglycemia/hypometabolism contributes to the development of AD or is a response of reduced neuronal activity remains unclear. To investigate the causal relationship, we cultured the differentiated N2a neuroblastoma cells in glucose/pyruvate-deficient media (GDM). Shortly after the N2a cells cultured in the GDM, the mitochondria membrane potential was reduced and the AMP-activated-proteinkinase (AMPK), an energy sensor, was activated. Treatment of GDM not only increased the levels of tau phosphorylation at Ser²⁶² and Ser³⁹⁶, but also increased the levels of active forms of GSK3α and GSK3β, two known kinases for tau phosphorylation, of the N2a cells. The levels of activated Akt, a mediator downstream to AMPK and upstream to GSK3α/β, were reduced by the GDM treatment. The effect of hypoglycemia was further examined in vivo by intracerebroventricular (icv) injection of streptozotocin (STZ) to the Wistar rats. STZ selectively injuries glucose transporter type 2-bearing cells which are primarily astrocytes in the rat brain, hence, interrupts glucose transportation from blood vessel to neuron. STZicv injection induced energy crisis in the brain regions surrounding the ventricles, as indicated by higher pAMPK levels in the hippocampus, but not cortex far away from the ventricles. STZ-icv treatment increased the levels of phosphorylated tau and activated GSK3β, but decreased the levels of activated Akt in the hippocampus. The hippocampus-dependent spatial learning and memory was impaired by the STZ-icv treatment. In conclusion, our works suggest that hypoglycemia enhances the AMPK-Akt-GSK3 pathway and leads to tau hyperphosphorylation.

Keywords: Alzheimer’s disease, hypoglycemia, AMPK, Akt, GSK3, tau

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