Glimepiride mitigates tauopathy and neuroinflammation in P301S transgenic mice: role of AKT/GSK3β signaling

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Institute of Global Health & Human Ecology

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Mennatallah O Zaki, S El-Desouky, Doaa A Elsherbiny, Mohamed Salama, Samar S Azab

Document Type

Research Article

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Publication Date

Summer 8-3-2022




Background and objective: Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study. Methods: P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests. Results: GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3β, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels.

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