Cooexpression of FTDP-17 tau and GSK-3beta in transgenic mice induce tau polymerization and neurodegeneration.
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-3beta (Tet/GSK-3beta mice), with transgenic mice expressing Tau with a triple FTDP-17 mutation which develop prefibrillar tau-aggregates (VLW mice). Tet/GSK-3beta/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-3beta mice develops much faster in Tet/GSK-3beta/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.
Engel
Tobias
T
Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Fac. Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Lucas
José J
JJ
Gómez-Ramos
Pilar
P
Moran
María A
MA
Avila
Jesús
J
Hernández
Félix
F
D000818:Animals; D052160:Benzothiazoles; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D018891:Dentate Gyrus / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009410:Nerve Degeneration / Q000175:diagnosis*; D016900:Neurofilament Proteins / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation; D013844:Thiazoles; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D052160:Benzothiazoles; D015415:Biomarkers; C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3