Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer's disease mutants of APP and presenilin-1.
To study the role of Abeta 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 Abeta, 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 Abeta deposits. The phosphorylation status of this somatodendritic tau was similar in the two transgenic lines. The Abeta 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 Abeta deposits, however, were associated to marked changes in cytoskeletal organisation and in tau phosphorylation in adjacent dystrophic neurites.
Boutajangout
Allal
A
Laboratory of Histology and Neuropathology, Université Libre de Bruxelles, Campus Erasme, 1070 Brussels, Belgium.
Authelet
Michèle
M
Blanchard
Véronique
V
Touchet
N
N
Tremp
Gunter
G
Pradier
Laurent
L
Brion
Jean-Pierre
JP
D008841:Actin Cytoskeleton / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D003599:Cytoskeleton / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008870:Microtubules / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D016501:Neurites / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D053764:Presenilin-1; D016875:tau Proteins / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins