Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice.
The hypothesis that amyloid pathology precedes and induces the tau pathology of Alzheimer's disease is experimentally supported here through the identification of GSK-3 isozymes as a major link in the signaling pathway from amyloid to tau pathology. This study compares two novel bigenic mouse models: APP-V717I x Tau-P301L mice with combined amyloid and tau pathology and GSK-3beta x Tau-P301L mice with tauopathy only. Extensive and remarkable parallels were observed between these strains including 1) aggravation of tauopathy with highly fibrillar tangles in the hippocampus and cortex; 2) prolonged survival correlated to alleviated brainstem tauopathy; 3) development of severe cognitive and behavioral defects in young adults before the onset of amyloid deposition or tauopathy; and 4) presence of pathological phospho-epitopes of tau, including the characteristic GSK-3beta motif at S396/S404. Both GSK-3 isozymes were activated in the brain of parental APP-V717I amyloid mice, even at a young age when cognitive and behavioral defects are evident but before amyloid deposition. The data indicate that amyloid induces tauopathy through activation of GSK-3 and suggest a role for the kinase in maintaining the functional integrity of adult neurons.
Terwel
Dick
D
Experimental Genetics Group, Department Human Genetics, Katholieke Universiteit Leuven-Campus Gasthuisberg ON1-06.602, B-3000 Leuven, Belgium.
Muyllaert
David
D
Dewachter
Ilse
I
Borghgraef
Peter
P
Croes
Sophie
S
Devijver
Herman
H
Van Leuven
Fred
F
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000682:Amyloid / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D003071:Cognition / Q000502:physiology; D003433:Crosses, Genetic; D018450:Disease Progression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006579:Heterozygote; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics*
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D011505:Protein-Tyrosine Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3