Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer’s disease mutants of APP and presenilin-1 Allal Boutajangout, a Miche `le Authelet, a Ve ´ronique Blanchard, b N. Touchet, c Gunter Tremp, b,c Laurent Pradier, b and Jean-Pierre Brion a, * a Laboratory of Histology and Neuropathology, Universite ´ Libre de Bruxelles, Campus Erasme, 1070 Brussels, Belgium b Neurodegenerative Disease Group, Aventis Pharma, Centre de Recherche de Vitry-Alfortville, 94403 Vitry-sur-Seine, France c Functional Genomics Department, Aventis Pharma, Centre de Recherche de Vitry-Alfortville, 94403 Vitry-sur-Seine, France Received 2 January 2003; revised 8 July 2003; accepted 12 September 2003 To study the role of AB amyloid deposits in the generation of cytoskeletal lesions, we have generated a transgenic mouse line coexpressing in the same neurons a wild-type human tau isoform (0N3R), a mutant form of APP (751SL) and a mutant form of PS1 (M146L). These mice developed early cerebral extracellular deposits of AB, starting at 2.5 months. A somatodendritic neuronal accumulation of transgenic tau protein was observed in tau only and in tau/PS1/APP transgenic mice, including in neurons adjacent to AB deposits. The phosphorylation status of this somatodendritic tau was similar in the two transgenic lines. The AB deposits were surrounded by a neuritic reaction composed of axonal dystrophic processes, immunoreactive for many phosphotau epitopes and for the human tau transgenic protein. Ultrastructural observation showed in these dystrophic neurites a disorganisation of the microtubule and the neurofilament network but animals that were observed up to 18 months of age did not develop neurofibrillary tangles. These results indicate that overexpression of mutant PS1, mutant APP and of wild- type human tau were not sufficient per se to drive the formation of neurofibrillary tangles in a transgenic model. The AB deposits, however, were associated to marked changes in cytoskeletal organisation and in tau phosphorylation in adjacent dystrophic neurites. D 2003 Elsevier Inc. All rights reserved. Keywords: Transgenic; Tau; Presenilin 1; APP; Mutation; Alzheimer Introduction The two neuropathological hallmark lesions observed in the brain of patients with Alzheimer’s disease (AD) are the senile plaques and the neurofibrillary tangles. The main component of senile plaques is an extracellular amyloid deposit made of a 39 to 43 amino acids peptide (the Ah peptide), generated by proteolysis from the amyloid precursor protein (APP). Neurofi- brillary tangles are constituted of bundles of abnormal filaments called paired helical filaments (PHF), found in neurons and in dystrophic neurites associated to Ah deposits. These PHF are composed of highly phosphorylated forms of the microtubule- associated protein tau. It is believed that the high degree of phosphorylation of tau is a critical event linked to microtubule disorganisation, generation of neurofibrillary lesions, and neuro- nal cell death and dysfunction (Goedert et al., 1997). In addition to sporadic cases, a small percentage of familial Alzheimer’s disease (FAD) cases are caused by autosomal dom- inant mutations of the APP gene or, more frequently, of the presenilin-1 (PS1) and PS2 genes (for a review, see Czech et al., 2000). Mutations in APP and PS1 have been shown to increase the production of Ah and of the longest forms of Ah (e.g. Ah1– 42) that aggregate more readily into amyloid fibres. In patients affected with pathogenic PS1 or APP mutations, numerous neurofibrillary tangles are also observed in addition to abundant Ah deposits, suggesting that these mutations might also sensitise neurons to the formation of neurofibrillary tangles. The Ah deposits might also be directly responsible for the generation of neurofibrillary tangles (Hardy, 1999). The molecular relationship between the formation of senile plaques and NFT might be experimentally investigated in an in vivo model of AD that would be expected to develop both senile plaques and neurofibrillary tangles. The development of Ah amyloid deposits in in vivo models has been successfully achieved in transgenic models overexpressing mutated forms of APP (Games et al., 1995; Hsiao et al., 1996; Sturchler-Pierrat et al., 1997) and is greatly accelerated in transgenic models over- expressing both mutated forms of APP and PS1 (Borchelt et al., 1997; Holcomb et al., 1998). Neurofibrillary tangles were, however, not observed in these transgenic lines. However, transgenic mouse lines expressing a mutated form of tau identi- fied in familial forms of fronto-temporal dementia were found to develop neurofibrillary tangles in the absence of Ah deposits 0969-9961/$ - see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2003.09.007 * Corresponding author. Laboratory of Histology and Neuropathology, School of Medicine, Universite ´ Libre de Bruxelles, 808 route de Lennik, Bldg. C-10, 1070 Brussels, Belgium. Fax: +32-2-5554121. E-mail address: jpbrion@ulb.ac.be (J.-P. Brion). Available online on ScienceDirect (www.sciencedirect.com.) www.elsevier.com/locate/ynbdi Neurobiology of Disease 15 (2004) 47 – 60