title: Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice.
abstract: 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.
authors.affiliation: Experimental Genetics Group, Department Human Genetics, Katholieke Universiteit Leuven-Campus Gasthuisberg ON1-06.602, B-3000 Leuven, Belgium.
authors.forename: Dick
authors.initials: D
authors.lastname: Terwel
authors.forename: David
authors.initials: D
authors.lastname: Muyllaert
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.forename: Peter
authors.initials: P
authors.lastname: Borghgraef
authors.forename: Sophie
authors.initials: S
authors.lastname: Croes
authors.forename: Herman
authors.initials: H
authors.lastname: Devijver
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
mesh_terms: 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*
chemical_list: 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