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Calcium influx recruits an additional class of kinases to hyperphosphorylate tau
T B Shea1, E P Klinger, C M Cressman
1Center for Cellular Neurobiology, University of Massachusetts at Lowell 01854, USA.
Abstract:
SH-SY-5Y human neuroblastoma cells were treated with combinations of the kinase inhibitors HA-1004, W-7 and H-7 and calcium ionophore A23187. Microdensitometric analyses revealed that, in the absence of ionophore-mediated calcium influx, PHF-1 levels were reduced by approximately half in cultures treated with HA-1004 or W-7, but were not reduced by H-7. By contrast, the doubling in PHF-1 immunoreactivity that resulted following ionophore treatment was prevented by all three inhibitors. These analyses demonstrate the recruitment of an additional kinase or kinases in tau phosphorylation following calcium influx, and underscore the possibility that de novo hyperactivation of calcium-dependent kinases may be involved in the early events that propagate PHF formation.
Insights
Calcium influx activates kinases, increasing tau phosphorylation (PHF-1 levels). Kinase inhibitors blocked this increase, suggesting calcium-dependent kinases are key in early tau pathology and PHF formation.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Tau hyperphosphorylation is a hallmark of neurodegenerative diseases like Alzheimer's.
- Calcium signaling is implicated in neuronal function and dysfunction.
- Specific kinases play roles in tau phosphorylation, but their precise involvement in calcium-mediated events is not fully understood.
Purpose of the Study:
- To investigate the role of calcium influx in tau phosphorylation.
- To identify kinases involved in calcium-mediated tau hyperphosphorylation.
- To explore the potential involvement of calcium-dependent kinases in the early stages of PHF formation.
Main Methods:
- SH-SY-5Y human neuroblastoma cells were utilized.
- Cells were treated with kinase inhibitors (HA-1004, W-7, H-7) and calcium ionophore A23187.
- Microdensitometric analyses were performed to quantify PHF-1 immunoreactivity.
Main Results:
- In the absence of calcium influx, HA-1004 and W-7 reduced PHF-1 levels, while H-7 did not.
- Ionophore-induced doubling of PHF-1 immunoreactivity was prevented by all three inhibitors.
- These findings suggest additional kinases are recruited during calcium influx.
Conclusions:
- Calcium influx activates specific kinases, leading to increased tau phosphorylation.
- Inhibition of these calcium-dependent kinases can prevent ionophore-induced tau hyperphosphorylation.
- De novo hyperactivation of calcium-dependent kinases may be crucial in the early propagation of PHF formation in neurodegeneration.