LiCl attenuates thapsigargin-induced tau hyperphosphorylation by inhibiting GSK-3β in vivo and in vitro
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Updated: Jun 2, 2026
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Zheng-Qi Fu1, Ying Yang, Jie Song
1Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Abnormal hyperphosphorylation of microtubule-associated protein tau is involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress is indicated to play an important role in neurodegeneration and activation of glycogen synthase kinase-3β (GSK-3β), an integral kinase in tau phosphorylation. To explore the effect of ER stress on tau phosphorylation, we treated cultured cells (HEK293 and SH-SY5Y cells) and rat brain with thapsigargin, an ER stress inducer. We found that the phosphorylation level of tau was significantly increased after thapsigargin treatment. By using a cell-free reconstitution system, we also observed that co-culture of the thapsigargin-treated ER fraction from HEK293/wt (without tau) with cytoplasm prepared from HEK293/tau induced an increased tau phosphorylation. Concurrently, activation of GSK-3β as evidenced by an increased phospho-GSK-3β at Tyr-216 and decreased phospho-GSK-3β at Ser-9 both in vitro and in vivo was detected. Application of lithium chloride, a GSK-3β inhibitor, could efficiently attenuate the thapsigargin-induced tau hyperphosphorylation with suppressed activation of GSK-3β in cell cultures and rat brains. Our data provide further evidence supporting the role of ER stress in tau hyperphosphorylation and the protective role of lithium.
Insights
Endoplasmic reticulum (ER) stress significantly increases tau phosphorylation, a key factor in Alzheimer's disease. Lithium chloride treatment effectively reduces this hyperphosphorylation by inhibiting GSK-3β activation.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Abnormal tau hyperphosphorylation is implicated in neurodegenerative diseases like Alzheimer's disease (AD).
- Endoplasmic reticulum (ER) stress is recognized as a significant contributor to neurodegeneration.
- ER stress can activate glycogen synthase kinase-3β (GSK-3β), a kinase crucial for tau phosphorylation.
Purpose of the Study:
- To investigate the impact of ER stress on tau phosphorylation.
- To elucidate the role of GSK-3β activation in ER stress-induced tau hyperphosphorylation.
- To evaluate the potential therapeutic effect of lithium chloride on ER stress-mediated tau pathology.
Main Methods:
- Treatment of cultured cells (HEK293, SH-SY5Y) and rat brains with thapsigargin, an ER stress inducer.
- Utilizing a cell-free reconstitution system to assess ER fraction and cytoplasmic effects on tau phosphorylation.
- Measuring GSK-3β activation through specific phosphorylation site analysis (Tyr-216, Ser-9).
- Administering lithium chloride, a GSK-3β inhibitor, to evaluate its protective effects.
Main Results:
- Thapsigargin treatment significantly elevated tau phosphorylation levels in both cell cultures and rat brains.
- ER stress induced activation of GSK-3β, evidenced by increased p-GSK-3β (Tyr-216) and decreased p-GSK-3β (Ser-9).
- Lithium chloride administration successfully attenuated thapsigargin-induced tau hyperphosphorylation and suppressed GSK-3β activation.
Conclusions:
- ER stress plays a critical role in promoting tau hyperphosphorylation.
- GSK-3β is a key mediator linking ER stress to tau pathology.
- Lithium chloride demonstrates a protective effect against ER stress-induced tau hyperphosphorylation, highlighting its therapeutic potential.
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