engleski

Follow up of hippocampal tau protein changes in rat model of sporadic Alzheimer's disease

Objectives: Neurofibrillar tangles associated with tau protein hyperphosphorylation induced by glycogen synthase kinase 3 (GSK3) are one of the major hallmarks of sporadic Alzheimer’s disease (sAD). The appearance and time course of tau protein hyperphosphorylation, impossible to investigate in humans, can be explored in experimental sAD model like streptozotocin- intracerebroventricularly (STZ-icv) treated rat. We aimed to compare early (two weeks) and late (nine months) hippocampal tau protein and GSK3 changes following the experimental sAD induction. Methods: Three months old male Wistar rats were injected with STZ (3mg/kg) bilaterally into the lateral ventricles while control animals received vehicle only. Cognitive functions were tested by Morris Water Maze Swimming Test before sacrifice, two weeks and nine months after STZ-icv treatment, respectively. Protein expression of total tau, phospho-tau (p-tau), phospho-GSK3α and β (pGSK3α and pGSK3β) and total GSK3 was measured by SDS- PAGE electrophoresis, followed by Western blot analysis in hippocampus (HPC), and data analysed by Mann-Whitney U test (p<0, 05). Results: Two weeks following the STZ-icv treatment only p- tau protein and pGSK3β expression was found significantly decreased (-25.6% and -40%, respectively), while after nine months, total tau protein and pGSK3β expression was found decreased (-31.8% and -45.1%, respectively) and total GSK3β expression increased (+49.9%). These changes were associated with decreased p/total tau ratio after two weeks, which after nine months was found highly increased (+51.3%). Contrary to that, p/total GSK3β ratio has appeared decreased already after two weeks (-41.7%) and continued to decrease to -62.6% after nine months. Cognitive deficit found after two weeks mildly deteriorated nine months after STZ-icv application. Conclusion: Decreased p/total tau protein ratio in relation to increased activity of GSK3β, indirectly assessed by decreased p/total GSK3 β ratio, suggests that acute changes of tau protein phosphorylation are mediated by kinase/phosphatase imbalance other than GSK3β, while in long term increased p/total tau ratio seems to be in line with the increased activity of GSK3β found up to nine months after STZ-icv induced experimental sAD presented here and in our previous research. Acknowledgement: Supported by MZOŠ (108-1080003-0020) and DAAD projects.

glycogen synthase kinase 3; streptozotocin; tau protein

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