Inhibition of protein phosphatase 2A overrides tau protein kinase I/glycogen synthase kinase 3 beta and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse.

Abstract

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brain. Starvation of adult mice induces tau hyperphosphorylation at many paired helical filaments sites and with a similar regional selectivity as those in AD, suggesting that a common mechanism may be mobilized. Here we investigated the mechanism of starvation-induced tau hyperphosphorylation in terms of tau kinases and Ser/Thr protein phosphatases (PP), and the results were compared with those reported in AD brain. During starvation, tau hyperphosphorylation at specific epitopes was accompanied by decreases in tau protein kinase I/glycogen synthase kinase 3 beta (TPKI/GSK3 beta), cyclin-dependent kinase 5 (cdk5), and PP2A activities toward tau. These results demonstrate that the activation of TPKI/GSK3 beta and cdk5 is not necessary to obtain hyperphosphorylated tau in vivo, and indicate that inhibition of PP2A is likely the dominant factor in inducing tau hyperphosphorylation in the starved mouse, overriding the inhibition of key tau kinases such as TPKI/GSK3 beta and cdk5. Furthermore, these data give strong support to the hypothesis that PP2A is important for the regulation of tau phosphorylation in the adult brain, and provide in vivo evidence in support of a central role of PP2A in tau hyperphosphorylation in AD.

• Authors: E Planel, K Yasutake, S C Fujita, K Ishiguro
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 36 Pg. 34298-306 (Sep 07 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11441005 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Proteins
• Okadaic Acid
• Cyclin-Dependent Kinase 5
• Protein Serine-Threonine Kinases
• Calcium-Calmodulin-Dependent Protein Kinases
• CDK5 protein, human
• Cdk5 protein, mouse
• Cyclin-Dependent Kinases
• Glycogen Synthase Kinase 3
• tau-protein kinase
• Phosphoprotein Phosphatases
• Protein Phosphatase 2
• Lithium Chloride

Topics

• Alzheimer Disease (metabolism)
• Animals
• Blotting, Western
• Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
• Cyclin-Dependent Kinase 5
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Electrophoresis, Polyacrylamide Gel
• Enzyme Inhibitors (pharmacology)
• Food Deprivation
• Glycogen Synthase Kinase 3
• Hippocampus (metabolism)
• Humans
• Lithium Chloride (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Biological
• Okadaic Acid (pharmacology)
• Phosphoprotein Phosphatases (antagonists & inhibitors)
• Phosphorylation
• Protein Phosphatase 2
• Protein Serine-Threonine Kinases (metabolism)
• Proteins (metabolism)
• Time Factors
• Up-Regulation