Here we have tested whether tau modification either by point mutation or by hyperphosphorylation can exert maximal pathogenic effects or if, on the contrary, both types of tau modifications can act synergistically to induce neuropathology. For this, we have combined transgenic mice overexpressing the enzyme GSK-3 beta (Tet/GSK-3 beta mice), with transgenic mice expressing Tau with a triple FTDP-17 mutation which develop prefibrillar tau-aggregates (VLW mice). Tet/GSK-3 beta/VLW transgenic mice show tau hyperphosphorylation in hippocampal neurons. This is accompanied by thioflavin-S staining, and formation of filaments similar in width to those found in tauophaties. Finally, the atrophy of the hippocampal dentate gyrus observed in Tet/GSK-3 beta mice develops much faster in TeUGSK-3 beta/VLW mice. All these morphological and biochemical data demonstrate that there is a synergistic contribution of both types of tau modifications and that the potential of GSK-3 inhibitors for AD therapeutics also extends to tauopathies caused by point mutations in tau gene. (c) 2005 Published by Elsevier Inc.
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Jackson, GR
Wiedau-Pazos, M
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Wiedau-Pazos, M
Sang, TK
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Sang, TK
Wagle, N
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Wagle, N
Brown, CA
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Brown, CA
Massachi, S
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Massachi, S
Geschwind, DH
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
机构:
Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Jackson, GR
Wiedau-Pazos, M
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Wiedau-Pazos, M
Sang, TK
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Sang, TK
Wagle, N
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Wagle, N
Brown, CA
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Brown, CA
Massachi, S
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA
Massachi, S
Geschwind, DH
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Univ Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USAUniv Calif Los Angeles, Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA