Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

Acta Pharmacologica Sinica, Apr 2015

Aim: The proteolytic cleavage of Tau is involved in Aβ-induced neuronal dysfunction and cell death. In this study, we investigated whether atorvastatin could prevent Tau cleavage and hence prevent Aβ1–42 oligomer (AβO)-induced neurotoxicity in cultured cortical neurons. Methods: Cultured rat hippocampal neurons were incubated in the presence of AβOs (1.25 μmol/L) with or without atorvastatin pretreatment. ATP content and LDH in the culture medium were measured to assess the neuronal viability. Caspase-3/7 and calpain protease activities were detected. The levels of phospho-Akt, phospho-Erk1/2, phospho-GSK3β, p35 and Tau proteins were measured using Western blotting. Results: Treatment of the neurons with AβO significantly decreased the neuronal viability, induced rapid activation of calpain and caspase-3/7 proteases, accompanied by Tau degradation and relatively stable fragments generated in the neurons. AβO also suppressed Akt and Erk1/2 kinase activity, while increased GSK3β and Cdk5 activity in the neurons. Pretreatment with atorvastatin (0.5, 1, 2.5 μmol/L) dose-dependently inhibited AβO-induced activation of calpain and caspase-3/7 proteases, and effectively diminished the generation of Tau fragments, attenuated synaptic damage and increased neuronal survival. Atorvastatin pretreatment also prevented AβO-induced decreases in Akt and Erk1/2 kinase activity and the increases in GSK3β and Cdk5 kinase activity. Conclusion: Atorvastatin prevents AβO-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting calpain- and caspase-mediated Tau cleavage.

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Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

Abstract Aim: The proteolytic cleavage of Tau is involved in Aβ-induced neuronal dysfunction and cell death. In this study, we investigated whether atorvastatin could prevent Tau cleavage and hence prevent Aβ1–42 oligomer (AβO)-induced neurotoxicity in cultured cortical neurons. Methods: Cultured rat hippocampal neurons were incubated in the presence of AβOs (1.25 μmol/L) with or without atorvastatin pretreatment. ATP content and LDH in the culture medium were measured to assess the neuronal viability. Caspase-3/7 and calpain protease activities were detected. The levels of phospho-Akt, phospho-Erk1/2, phospho-GSK3β, p35 and Tau proteins were measured using Western blotting. Results: Treatment of the neurons with AβO significantly decreased the neuronal viability, induced rapid activation of calpain and caspase-3/7 proteases, accompanied by Tau degradation and relatively stable fragments generated in the neurons. AβO also suppressed Akt and Erk1/2 kinase activity, while increased GSK3β and Cdk5 activity in the neurons. Pretreatment with atorvastatin (0.5, 1, 2.5 μmol/L) dose-dependently inhibited AβO-induced activation of calpain and caspase-3/7 proteases, and effectively diminished the generation of Tau fragments, attenuated synaptic damage and increased neuronal survival. Atorvastatin pretreatment also prevented AβO-induced decreases in Akt and Erk1/2 kinase activity and the increases in GSK3β and Cdk5 kinase activity. Conclusion: Atorvastatin prevents AβO-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting calpain- and caspase-mediated Tau cleavage. Introduction Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal accumulations of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) throughout cortical and limbic brain regions. Cognitive deficits in AD are believed to result from progressive synaptic dysfunction and neurodegeneration initiated by soluble amyloid β oligomers (AβOs) and further involving aggregates of hyperphosphorylated Tau1,2. AβOs, which are increasingly considered to act as proximal neurotoxins in AD, interact with glutamate receptors at the dendritic membrane, induce abnormal calcium influx and oxidative stress, block long-term potentiation (LTP), and facilitate long-term depression, ultimately leading to synapse failure3,4. It has recently been suggested that the deposition of Aβ might trigger a series of cellular events that lead to posttranslational changes in Tau followed by neurite degeneration2,5. Furthermore, experiments in both cultured rodent hippocampal neurons and transgenic mice demonstrate that Tau is intrinsically involved in Aβ-mediated neuronal dysfunction and cell death6,7. Taken together, the data suggest that there is an intrinsic relationship between Aβ and Tau dysfunction. It has been shown that the deposition of Aβ induced the activation of calpain-1 and caspase-3 proteases2,5,8. These proteases cleave Tau proteins at specific sites, generating toxic Tau fragments or enhancing the aggregation properties of Tau protein2,5,9. The activation of these proteases, Tau cleavage, and the extent of neurodegeneration are both time- and dose-dependent2,5,9. Inhibition of these proteases completely prevented the Tau proteolysis that leads to the generation of a 17-kDa fragment, significantly reducing Aβ-induced neuronal death2,5. Furthermore, hippocampal neurons transfected with 17-kDa Tau showed signs of degeneration, such as tortuous processes, varicosities along the neurites, and retraction of neuritic processes5. Collectively, these data suggest that a reduction in factors that prevent the activation of calpain and caspase-3, and hence Tau cleavage, could have some bearing in the pathophysiology of AD. Several prospective studies have indicated that statins could prevent the onset of AD10,11,12. A recent meta-analysis by Wong et al also showed that statins have preventive effects on AD13. Evidence from cell culture experiments and animal studies has suggested that statins have many pleiotropic effects, such as reducing Aβ production, suppressing inflammatory responses, protecting neurons from Aβ-induced neurotoxicity, apoptosis and oxidative stress, and promoting synaptogenesis14,15,16,17. Recently, a transgenic mouse model of tauopathy showed a reduction in NFTs in response to statin treatment in both early and late stages of disease progression18. It has been reported that statins reduce the number of phosphorylated Tau-positive neurites in aged amyloid precursor protein (APP) transgenic mice19. Atorvastatin is a member of the statin family. Clarke et al demonstrated that rats treated with atorvastatin for 3 weeks were protected against a deficiency in LTP caused by the acute injection of Aβ1–4220. Our previous results revealed that atorvastatin prevented AβO-induced synaptotoxicity, which leads to memory dysfunction through a p38MAPK-dependent pathway17. However, the mechanisms under (...truncated)


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Hai-juan Sui, Ling-ling Zhang, Zhou Liu, Ying Jin. Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage, Acta Pharmacologica Sinica, 2015, pp. 553-564, Issue: 36, DOI: 10.1038/aps.2014.161