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(American Journal of Pathology. 1999;154:255-270.)
© 1999 American Society for Investigative Pathology

Regular Articles

Transgenic Expression of the Shortest Human Tau Affects Its Compartmentalization and Its Phosphorylation as in the Pretangle Stage of Alzheimer's Disease

Jean-Pierre Brion* , Gunter Tremp and Jean-Noël Octave

From the Laboratory of Pathology and Electron Microscopy,* Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium; Rhône-Poulenc Rorer, Core Biotechnology Department, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France; and the Laboratory of Pharmacology, Université Catholique de Louvain, Brussels, Belgium

We have generated transgenic mice expressing the shortest human tau protein, the microtubule-associated protein that composes paired helical filaments in Alzheimer's disease. Transgenic tau transcripts and proteins were strongly expressed in neurons in the developing and adult brain. In contrast to the endogenous tau that progressively disappeared from neuronal cell bodies during development, the human transgenic tau remained abundant in cell bodies and dendrites of a subset of neurons in the adult. This somatodendritic transgenic tau was immunoreactive with antibodies to tau phosphorylated on Thr181 and Thr231 and with the conformation-dependent Alz50 antibody. A few astrocytes expressing the transgenic tau were strongly immunoreactive with antibodies to additional tau phosphorylation sites, ie, at Ser262/356 and Ser396/404. All of these phosphorylation sites have been identified in paired helical filaments-tau proteins. In electron microscopy, the transgenic tau was detected into microtubules in axons and in dendrites but not in cell bodies. Neurofibrillary tangles were not detected in transgenic animals examined up to the age of 19 months. These results indicate that transgenic manipulation of tau expression and intracellular targeting is sufficient per se to affect tau compartmentalization, phosphorylation, and conformation partly as it is observed at the pretangle stage in Alzheimer's disease.

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