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Okadaic acid induces hyperphosphorylation of tau independently of mitogen-activated protein kinase activation
1Kinsmen Laboratory, Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Abstract:
Hyperphosphorylation of the microtubule-associated protein tau is a characteristic of Alzheimer brain tissue. Recent in vitro data suggest that mitogen-activated protein kinase (MAPK), a proline-directed protein kinase, phosphorylates the sites on tau common to Alzheimer's disease. Using an okadaic acid-induced tau hyperphosphorylation model, we have tested the requirement for MAPK activity, using a specific inhibitor ¿PD098059 [2-(2'-amino-3'-methoxyphenyl)oxanaphthalen-4-one]¿ of the MAPK activator Mek1. Mobility shift, phosphoepitope analysis, and direct measurement of kinase activity indicated that the Mek1 inhibitor dose-dependently blocked basal and okadaic acid-induced MAPK activation. Despite a block of MAPK activation by this inhibitor, robust tau hyperphosphorylation was observed in response to okadaic acid. In addition, activation of MAPK by phorbol 12-myristate 13-acetate did not result in tau phosphorylation, indicating that in primary cultures of cortical neurons elevated MAPK activity is not sufficient to induce tau hyperphosphorylation.
Insights
Mitogen-activated protein kinase (MAPK) is not required for okadaic acid-induced tau hyperphosphorylation in Alzheimer's disease models. Elevated MAPK activity alone does not cause tau hyperphosphorylation in neuronal cultures.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Hyperphosphorylation of the microtubule-associated protein tau is a hallmark of Alzheimer's disease.
- Mitogen-activated protein kinase (MAPK) phosphorylates tau at Alzheimer's disease-relevant sites in vitro.
Purpose of the Study:
- To investigate the role of MAPK in okadaic acid-induced tau hyperphosphorylation.
- To determine if MAPK activation is sufficient to cause tau hyperphosphorylation in primary cortical neurons.
Main Methods:
- Utilized an okadaic acid-induced tau hyperphosphorylation model.
- Employed a specific Mek1 inhibitor (PD098059) to block MAPK activation.
- Assessed MAPK activation and tau phosphorylation using mobility shift, phosphoepitope analysis, and kinase activity assays.
Main Results:
- PD098059 effectively blocked basal and okadaic acid-induced MAPK activation in a dose-dependent manner.
- Despite MAPK inhibition, robust tau hyperphosphorylation occurred in response to okadaic acid.
- Activation of MAPK by phorbol 12-myristate 13-acetate did not lead to tau phosphorylation.
Conclusions:
- MAPK activation is not essential for okadaic acid-induced tau hyperphosphorylation.
- Elevated MAPK activity alone is insufficient to induce tau hyperphosphorylation in cortical neurons.
- Other signaling pathways likely mediate tau hyperphosphorylation in Alzheimer's disease models.