title: Susceptibility to GSK3β-induced tau phosphorylation differs between the young and aged hippocampus after Wnt signaling inhibition.
abstract: The abnormal phosphorylation of the microtubule-associated protein tau is a prominent aspect of Alzheimer's disease (AD). Considerable evidence suggests that glycogen synthase kinase 3β (GSK3β) and the protein phosphatase 2A (PP2A) are involved in normal and pathological tau phosphorylation. However, the mechanisms underlying a shift of the phosphorylation/dephosphorylation balance that leads to abnormal tau phosphorylation remains unknown. The canonical Wnt pathway negatively regulates GSK3β activity, and this signaling pathway has also been found to be dysregulated in the AD brain. Here, we report that the Wnt antagonist Dkk-1 selectively increases tau phosphorylation in the hippocampus of aged rats at Ser199/202, Ser396/404, and Ser214 sites. In the aged hippocampus, the inhibition of Wnt signaling is also accompanied by reduced PP2A activity. This study suggests that aging promotes tau hyperphosphorylation after Wnt inhibition, due to an imbalance between GSK3β and PP2A activities.
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México D.F., Mexico.
authors.forename: Pamela
authors.initials: P
authors.lastname: Salcedo-Tello
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México D.F., Mexico.
authors.forename: Karina
authors.initials: K
authors.lastname: Hernández-Ortega
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México D.F., Mexico.
authors.forename: Clorinda
authors.initials: C
authors.lastname: Arias
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000235:genetics; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000235:genetics*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C531384:Dkk1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; C489131:Mapt protein, rat; D051153:Wnt Proteins; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: Aging; GSK3β; PP2A; Wnt signaling; hippocampal slices; tau phosphorylation