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Updated: Dec 31, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Chronic hyperglycemia induces tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in
Rong Huang1, Sai Tian2, Haoqiang Zhang2
1Department of Endocrinology, Affiliated Zhongda Hospital of Southeast University, No. 87 DingJiaQiao Road, Nanjing, 210009, PR China; Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, PR China.
Objective:
Diabetes mellitus (DM) can increase the risk of cognitive dysfunction, but its exact mechanisms remain unclear. The involvement of aberrant O-GlcNAcylation has been identified in hyperglycemia and DM, as well as the pathogenesis of Alzheimer's disease via competition with tau phosphorylation. This study was designed to investigate the role of O-GlcNAcylation in diabetes-associated cognitive dysfunction (DACD).
Methods:
Fifteen-week old male KK-Ay mice were used as DACD models, and advanced glycation end product (AGE)-treated HT22 cells were used as a model of high glucose toxicity. Morris water maze tests, histological staining, real-time quantitative PCR, and Western blot were also applied.
Results:
Mice with DACD exhibited evident obesity, hyperinsulinemia, hyperglycemia, and impaired learning and memory function. O-GlcNAcylation levels decreased and tau phosphorylation levels at Ser396, Ser404, Thr212, and Thr231 increased in the hippocampus of mice with DACD, as well as in AGE-treated HT22 cells. Hypoglycemic therapy improved these anomalies and elevated O-GlcNAc transferase (OGT) levels in mice with DACD. OGT plasmid transfection in HT22 cells partially reversed AGE-induced decreases in O-GlcNAcylation levels and increased tau phosphorylation levels.
Conclusions:
Chronic hyperglycemia can induce tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro, which mediates DACD.
Insights
Diabetes-associated cognitive dysfunction involves decreased O-GlcNAcylation and increased tau phosphorylation. Lowering blood sugar improved these changes, suggesting O-GlcNAcylation is key to diabetes-related memory loss.
Area of Science:
- Neuroscience
- Endocrinology
- Biochemistry
Background:
- Diabetes mellitus (DM) is linked to cognitive dysfunction, but mechanisms are unclear.
- Aberrant O-GlcNAcylation is implicated in hyperglycemia, DM, and Alzheimer's disease pathogenesis.
- O-GlcNAcylation may compete with tau phosphorylation, a hallmark of neurodegenerative diseases.
Purpose of the Study:
- To investigate the role of O-GlcNAcylation in diabetes-associated cognitive dysfunction (DACD).
Main Methods:
- Utilized KK-Ay mice as DACD models and AGE-treated HT22 cells for high glucose toxicity.
- Employed Morris water maze tests, histological staining, qPCR, and Western blot analysis.
- Assessed O-GlcNAcylation and tau phosphorylation levels in hippocampal and cellular models.
Main Results:
- DACD mice showed obesity, hyperinsulinemia, hyperglycemia, and impaired memory.
- Hippocampal O-GlcNAcylation decreased, while tau phosphorylation increased in DACD mice and AGE-treated cells.
- Hypoglycemic therapy normalized cognitive function and increased O-GlcNAc transferase (OGT) levels in mice.
- OGT plasmid transfection partially reversed AGE-induced changes in HT22 cells.
Conclusions:
- Chronic hyperglycemia downregulates OGT-mediated O-GlcNAcylation.
- This downregulation leads to tau hyperphosphorylation, mediating diabetes-associated cognitive dysfunction.
- O-GlcNAcylation represents a potential therapeutic target for DACD.
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