Abstract
In the normal brain, tau protein is phosphorylated at a number of proline- and non-proline directed sites, which reduce tau microtubule binding and thus regulate microtubule dynamics. In Alzheimer disease (AD), tau is abnormally hyperphosphorylated, leading to neurofibrillary tangle formation and microtubule disruption, suggesting a loss of regulatory mechanisms controlling tau phosphorylation. Early growth response 1 (Egr-1) is a transcription factor that is significantly up-regulated in AD brain. The pathological significance of this up-regulation is not known. In this study, we found that lentivirus-mediated overexpression of Egr-1 in rat brain hippocampus and primary neurons in culture activates proline-directed kinase Cdk5, inactivates PP1, promotes tau phosphorylation at both proline-directed Ser(396/404) and non-proline-directed Ser(262) sites, and destabilizes microtubules. Furthermore, in Egr-1(-/-) mouse brain, Cdk5 activity was decreased, PP1 activity was increased, and tau phosphorylation was reduced at both proline-directed and non-proline-directed sites. By using nerve growth factor-exposed PC12 cells, we determined that Egr-1 activates Cdk5 to promote phosphorylation of tau and inactivates PP1 via phosphorylation. When Cdk5 was inhibited, tau phosphorylation at both proline- and non-proline directed sites and PP1 phosphorylation were blocked, indicating that Egr-1 acts through Cdk5. By using an in vitro kinase assay and HEK-293 cells transfected with tau, PP1, and Cdk5, we found that Cdk5 phosphorylates Ser(396/404) directly. In addition, by phosphorylating and inactivating PP1, Cdk5 promotes tau phosphorylation at Ser(262) indirectly. Our results indicate that Egr-1 is an in vivo regulator of tau phosphorylation and suggest that in AD brain increased levels of Egr-1 aberrantly activate an Egr-1/Cdk5/PP1 pathway, leading to accumulation of hyperphosphorylated tau, thus destabilizing the microtubule cytoskeleton.
Highlights
Recent studies suggest that -amyloid deposition may occur early and initiate pathological events including tau phosphorylation [4]
Our data indicate that early growth response 1 (Egr-1) is an in vivo regulator of tau protein phosphorylation and suggest that increased levels of Egr-1 in Alzheimer disease (AD) brain play a role in neurofibrillary tangles (NFTs) pathology
When a similar experiment was performed using a polyclonal antibody directed to human Egr-1, the relative Egr-1 protein levels in AD brain temporal cortex and hippocampus were 1.8and 1.9-fold higher, respectively, than in normal brain
Summary
Recent studies suggest that -amyloid deposition may occur early and initiate pathological events including tau phosphorylation [4]. A number of independent studies have shown that curcumin is an inhibitor of Egr-1 activity in vivo and have suggested that inhibition of Egr-1 may be a therapeutic approach for AD (44 –50) These observations together argue that Egr-1 is up-regulated in AD brain and raise questions regarding the pathophysiological significance of this up-regulation. We demonstrate that targeted expression of Egr-1 in rat brain hippocampus or in primary hippocampal neurons in culture promotes tau hyperphosphorylation and destabilizes the microtubule cytoskeleton by a mechanism involving Cdk and protein phosphatase 1 (PP1). Our data indicate that Egr-1 is an in vivo regulator of tau protein phosphorylation and suggest that increased levels of Egr-1 in AD brain play a role in NFT pathology
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