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The Journal of Neuroscience, March 3, 2004, 24(9):2304-2312; doi:10.1523/JNEUROSCI.4162-03.2004

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Cellular/Molecular
Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease

Gloria Lee,¹ Ramasamy Thangavel,² Vandana M. Sharma,¹ Joel M. Litersky,¹ Kiran Bhaskar,¹ Sandy M. Fang,¹ Lana H. Do,¹ Athena Andreadis,⁴ Gary Van Hoesen,² and Hanna Ksiezak-Reding³

Departments of ¹Internal Medicine and ²Anatomy and Cell Biology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, ³Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, and ⁴Department of Biomedical Sciences, Shriver Center, University of Massachusetts Medical School, Waltham, Massachusetts 02452

The abnormal phosphorylation of tau protein on serines and threonines is a hallmark characteristic of the neurofibrillary tangles of Alzheimer's disease (AD). The discovery that tau could be phosphorylated on tyrosine and evidence that A signal transduction involved tyrosine phosphorylation led us to question whether tyrosine phosphorylation of tau occurred during the neurodegenerative process. In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. By developing both polyclonal and monoclonal probes specific for phospho-tyr18, we found that the phosphorylation of tau at tyr18 occurred at early developmental stages in mouse but was absent in the adult. Our phosphospecific probes also revealed that paired helical filament preparations exhibited phospho-tyr18 reactivity that was sensitive to phosphotyrosine-specific protein phosphatase treatment. Moreover, immunocytochemical studies indicated that tyrosine phosphorylated tau was present in the neurofibrillary tangles in AD brain. However, the staining pattern excluded neuropil threads and dystrophic neurites indicating that tyrosine phosphorylated tau was distributed in AD brain in a manner dissimilar from other abnormally phosphorylated tau. We also found evidence suggesting that differentially phosphorylated tau existed within degenerating neurons. Our data add new support for a role for fyn in the neurodegenerative process.

Key words: tau; fyn; tyrosine phosphorylation; neurofibrillary tangles; phosphospecific antibodies; Alzheimer's disease

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Received Sep 10, 2003; revised January 12, 2004; accepted January 12, 2004.

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