title: Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice.
abstract: 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.
authors: Laboratory of Histology and Neuropathology, Université Libre de Bruxelles, School of Medicine, 808, Route de Lennik, Bldg. G, 1070 Brussels, Belgium.
authors: Karelle
authors: K
authors: Leroy
authors: Alexis
authors: A
authors: Bretteville
authors: Katharina
authors: K
authors: Schindowski
authors: Emmanuel
authors: E
authors: Gilissen
authors: Michèle
authors: M
authors: Authelet
authors: Robert
authors: R
authors: De Decker
authors: Zehra
authors: Z
authors: Yilmaz
authors: Luc
authors: L
authors: Buée
authors: Jean-Pierre
authors: JP
authors: Brion
mesh_terms: D000818:Animals; D001284:Atrophy / Q000473:pathology; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009069:Movement Disorders / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016900:Neurofilament Proteins; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
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