Article
- The EMBO Journal (2001) 20, 27 - 39
- doi:10.1093/emboj/20.1.27
Decreased nuclear 
-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3 conditional transgenic mice
José J. Lucas1,4, Félix Hernández1,4, Pilar Gómez-Ramos2, María A. Morán2, René Hen3 and Jesús Avila1
- Centro de Biología Molecular 'Severo Ochoa', CSIC/Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Departamento de Morfología, Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Center for Neurobiology and Behavior, Columbia University, New York, NY, USA
- J.J.Lucas and F.Hernández contributed equally to this work
Correspondence to:
Jesús Avila, E-mail: javila@cbm.uam.es
Received 23 August 2000; Accepted 13 November 2000; Revised 18 October 2000
Abstract
Glycogen synthase kinase-3
(GSK-3) has been postulated to mediate Alzheimer's disease tau hyperphosphorylation, -amyloid-induced neurotoxicity and presenilin-1 mutation pathogenic effects. By using the tet-regulated system we have produced conditional transgenic mice overexpressing GSK-3 in the brain during adulthood while avoiding perinatal lethality due to embryonic transgene expression. These mice show decreased levels of nuclear -catenin and hyperphosphorylation of tau in hippocampal neurons, the latter resulting in pretangle-like somatodendritic localization of tau. Neurons displaying somatodendritic localization of tau often show abnormal morphologies and detachment from the surrounding neuropil. Reactive astrocytosis and microgliosis were also indicative of neuronal stress and death. This was further confirmed by TUNEL and cleaved caspase-3 immunostaining of dentate gyrus granule cells. Our results demonstrate that in vivo overexpression of GSK-3 results in neurodegeneration and suggest that these mice can be used as an animal model to study the relevance of GSK-3 deregulation to the pathogenesis of Alzheimer's disease.
Keywords:
- Alzheimer's disease,
- -catenin,
- conditional transgenic mice,
- GSK-3,
- tau phosphorylation
