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(American Journal of Pathology. 2004;165:1643-1652.)
© 2004 American Society for Investigative Pathology

Induction of Inflammatory Mediators and Microglial Activation in Mice Transgenic for Mutant Human P301S Tau Protein

Arianna Bellucci*{dagger}, Andrew J. Westwood*, Esther Ingram*, Fiorella Casamenti{dagger}, Michel Goedert{ddagger} and Maria Grazia Spillantini*

From the Department of Clinical Neurosciences,* Brain Repair Centre, University of Cambridge, Cambridge, United Kingdom; the Medical Research Council Laboratory of Molecular Biology,{ddagger} Cambridge, United Kingdom; and the Department of Preclinical and Clinical Pharmacology,{dagger} University of Florence, Florence, Italy

Mice transgenic for human P301S tau protein exhibit many characteristics of the human tauopathies, including the formation of abundant filaments made of hyperphosphorylated tau protein and neurodegeneration leading to nerve cell loss. At 5 months of age, the pathological changes are most marked in brainstem and spinal cord. Here we show that these changes are accompanied by marked neuroinflammation. Many tau-positive nerve cells in brainstem and spinal cord were strongly immunoreactive for interleukin-1ß and cyclooxygenase-2, indicating induction and overproduction of proinflammatory cytokines and enzymes. In parallel, numerous activated microglial cells were present throughout brain and spinal cord of transgenic mice, where they concentrated around tau-positive nerve cells. These findings suggest that inflammation may play a significant role in the events leading to neurodegeneration in the tauopathies and that anti-inflammatory compounds may have therapeutic potential.




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