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Originally published online as doi:10.2353/ajpath.2007.070345 on August 9, 2007

Published online before print August 9, 2007
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(American Journal of Pathology. 2007;171:976-992.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070345

Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice

Karelle Leroy*, Alexis Bretteville{dagger}, Katharina Schindowski{dagger}, Emmanuel Gilissen*, Michèle Authelet*, Robert De Decker*, Zehra Yilmaz*, Luc Buée{dagger} and Jean-Pierre Brion*

From the Laboratory of Histology, Neuroanatomy, and Neuropathology,* School of Medicine, Université Libre de Bruxelles, Brussels, Belgium; and Inserm U837 and Institut de Médecine Prédictive et Recherche Thérapeutique,{dagger} Jean-Pierre Aubert Research Centre, Faculté de Médecine, Lille, France

Neurodegenerative diseases characterized by brain and spinal cord involvement often show widespread accumulations of tau aggregates. We have generated a transgenic mouse line (Tg30tau) expressing in the forebrain and the spinal cord a human tau protein bearing two pathogenic mutations (P301S and G272V). These mice developed age-dependent brain and hippocampal atrophy, central and peripheral axonopathy, progressive motor impairment with neurogenic muscle atrophy, and neurofibrillary tangles and had decreased survival. Axonal spheroids and axonal atrophy developed early before neurofibrillary tangles. Neurofibrillary inclusions developed in neurons at 3 months and were of two types, suggestive of a selective vulnerability of neurons to form different types of fibrillary aggregates. A first type of tau-positive neurofibrillary tangles, more abundant in the forebrain, were composed of ribbon-like 19-nm-wide filaments and twisted paired helical filaments. A second type of tau and neurofilament-positive neurofibrillary tangles, more abundant in the spinal cord and the brainstem, were composed of 10-nm-wide neurofilaments and straight 19-nm filaments. Unbiased stereological analysis indicated that total number of pyramidal neurons and density of neurons in the lumbar spinal cord were not reduced up to 12 months in Tg30tau mice. This Tg30tau model thus provides evidence that axonopathy precedes tangle formation and that both lesions can be dissociated from overt neuronal loss in selected brain areas but not from neuronal dysfunction.




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