Research Article: Inhibition of Polo-like kinase 1 reduces beta-amyloid-induced neuronal cell death in Alzheimer’s disease

Date Published: September 13, 2011

Publisher: Impact Journals LLC

Author(s): Bing Song, Korbin Davis, X. Shawn Liu, Hyoung-gon Lee, Mark Smith, Xiaoqi Liu.

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Abstract

Alzheimer’s disease (AD) is a progressive and fatal brain disease, but the pathogenesis of AD is still not understood. Aberrant cell-cycle re-entry of neuronal cells is emerging as a potential pathological mechanism in AD. Polo-like kinase 1 (Plk1) is an established regulator of many cell cycle-related events. Interestingly, Plk1 is present in susceptible hippocampal and cortical neurons of AD patients but not age-matched controls. However, whether Plk1 is involved in the pathogenesis of AD remains elusive. In this study, we showed that Plk1 activity is elevated in AD patient brain as indicated by the increased phosphorylation signal of p150Glued, a Plk1-specific substrate. Furthermore, we demonstrated that Plk1 is elevated during the cell-cycle re-entry of neuronal cells in an in vitro cell-culture model. Significantly, inhibition of Plk1 kinase activity or depletion of Plk1 by RNAi reduces β-amyloid (Aβ)-induced neuronal cell death. These results validate Plk1 as a possible target for AD therapy.

Partial Text

Alzheimer’s disease (AD) is a fatal brain disease characterized by neuronal inflammation, neuronal cell loss, and decline of memory and recognition [1]. However, as the leading cause for death of dementia, the pathogenesis of AD is still far from being understood. Two hall marks of AD are senile plaques (SPs), which are mainly composed of β-amyloid peptide (Aβ) depositing outside of neuron bodies, and neurofibrillary tangles (NFTs), which are aggregates of hyperphosphorylated tau proteins that bind to microtubules within the neurons [1].

In adult tissues, Plk1 is not present or present at a very low level in non-proliferating tissue cells, such as brain, pancreas and heart [9]. However, Plk1 can be detected in brain tissues of patients with AD [13]. But whether Plk1 is involved in the pathogenesis of AD is still unknown. Considering the fact that Plk1 regulates cell cycle through phosphorylation of its substrates, we examined brain samples of AD patients by immunocytochemistry staining of phospho-Ser179-p150Glued. p150Glued, the largest subunit of the dynein/dynactin motor complex, plays important roles in many cellular processes, including neurodegeneration [15]. Our published work demonstrated that Plk1-mediated phosphorylation of p150Glued at Ser179 starts at interphase and that the phosphorylation event facilitates nuclear envelope breakdown at prophase of the cell cycle [14]. Phosphorylation of S179-p150Glued was detected in brain tissues of AD cases but not age-matched controls, indicating that not only Plk1 protein is expressed but its kinase activity is also activated in AD patient brains (Figure 1).

Plk1 is one of the best characterized Ser/Thr protein kinases. Genetic and biochemical studies have shown that Plk1 plays critical roles in many aspects of the cell cycle, such as DNA replication, G2 DNA damage recovery and mitotic entry [8, 10]. Consistent with these functions, the protein expression level of Plk1 starts to increase in S phase and peaks at G2/M [9]. Our published data have shown that Plk1 phosphorylates p150Glued at Ser179 during G2 phase [14]. Significantly, p150Glued is involved in neurodegenerative diseases [15]. In this study, we reported an increased level of phosphorylation of p150Glued-S179 in AD brains compared to age-matched controls, indicating that the elevated Plk1 protein in the neurons of AD patients is activated and able to phosphorylate its known substrates. Furthermore, our finding suggests that Plk1 might be a feasible therapeutic target for AD, as several small-molecule inhibitors of Plk1 are under clinical trials [8].

 

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