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P3‐133: Role of mTOR in tau translation and phosphorylation in SH‐SY5Y cell
Author(s) -
Tang Zhi,
Zhang Haiyan,
Wang Shan,
Winblad Bengt,
Pei Jin
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1573
Subject(s) - pi3k/akt/mtor pathway , phosphorylation , sh sy5y , translation (biology) , mtorc2 , rptor , chemistry , microbiology and biotechnology , signal transduction , biology , cancer research , biochemistry , messenger rna , neuroblastoma , cell culture , mtorc1 , gene , genetics
Background: Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly and is characterized by the presence of two characteristic pathological hallmarks: senile plaques and neurofibrillary tangles (NFTs). Senile plaques are composed of b-amyloid (As) peptides derived from sequential cleavage of the amyloid precursor protein. NFTs are composed mostly of abnormally hyperphosphorylated microtubule-associated protein tau. Egr-1, a zinc finger transcription factor regulates the transcription of a number of genes involved in immune response, differentiation, growth and development and plays a central role in the induction and maintenance of various vascular pathologies. The basal level of Egr-1 protein in the brainis relatively low, but it is rapidly and transiently induced by a large number of growth factors, cytokines, neurotransmitters, brain injury, ischemia, hypoxia and other stressors. Once induced, Egr-1 activates the expression of a number of genes including those involved in cell death and injury. Recent studies have shown that Egr-1 is up regulated in AD brain. The pathophysiological significance of this up regulation is not known. Methods: We have used rats and primary neurons in culture over expressiong Egr-1, Egr-1 -/mice, PC12 cells exposed to NGF and in vitro kinases assays. Results: We show that lentivirus-mediated over expression of Egr-1 in rat brain hippocampus and primary neurons in culture activates proline-directed kinaseCdk5, inactivates PP1, promotes tau phosphorylation at both proline-directed S and non-proline-directed S sites, and destabilizes microtubules. Furthermore, in Egr-1 mouse brain, Cdk5 activity is decreased, PP1 activity is increased and tau phosphorylation is reduced at both proline-directed and non-proline-directed sites. By using NGF-exposed PC12 cells, we determined that Egr-1 activates Cdk5 to promote phosphorylation of tau and inactivates PP1via phosphorylation. When Cdk5 is inhibited, tau phosphorylation at both prolineand non-proline directed sites as well as PP1 phosphorylation are blocked, indicating that Egr1 acts through Cdk5. By using an in vitro kinase assay and HEK-293 cells transfected with tau, PP1, and Cdk5, we show that Cdk5 phosphorylates Sdirectly. In addition, by phosphorylating and inactivating PP1, Cdk5 promotestau phosphorylation at S indirectly. Conclusions: Our results indicate that Egr-1 is an in vivo regulator of tauphosphorylation and suggest that in AD brain, increased levels of Egr-1aberrantly activates an Egr-1/Cdk5/PP1 pathway leading to accumulation of hyperphosphorylated tau, thus destabilizing the microtubule cytoskeleton.