Abstract
Abnormal tau hyperphosphorylation and deposition in Pick bodies is a major abnormality in Pick’s disease (PiD). This is associated with increased expression of the stress-activated protein kinase, p38 kinase, which has the capacity to phosphorylate tau in vitro. The present study has shown increased expression of phosphorylated p38 (p38-P), which does not cross-react with phospho-tau, in sarcosyl-insoluble fractions enriched in abnormal filaments, and hyperphosphorylated tau in the brain of two PiD cases obtained and processed with very short (less than 2 h) post-mortem delay. Immunohistochemical studies have shown p38-P co-localization in 90% of neurons with Pick bodies, whereas no positive cells are encountered in control brains processed in parallel. Moreover, p38-immunoprecipitated from sarcosyl-insoluble fractions in PiD brains is functionally active as it has the capacity to phosphorylate its specific substrate ATF-2. Combined biochemical, immunohistochemical and functional studies indicate that active p38 kinase is expressed in a very high percentage of Pick bodies, thus suggesting a critical role of this kinase in enhancing and perpetuating tau hyperphosphorylation in PiD.
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Acknowledgements
This work was supported in part with the contract QLRI-CT-2000-00066, and grants SAF2001-4681-E, FIS PI020004, and FIS PI030032. We wish to thank Dr. B. Dèrijard, CNRS, Université de Nice for providing GST-ATF-2 used for immunoprecipitation, and T. Yohannan for editorial assistance.
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Puig, B., Vinals, F. & Ferrer, I. Active stress kinase p38 enhances and perpetuates abnormal tau phosphorylation and deposition in Pick’s disease. Acta Neuropathol 107, 185–189 (2004). https://doi.org/10.1007/s00401-003-0793-z
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DOI: https://doi.org/10.1007/s00401-003-0793-z