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http://hdl.handle.net/1942/30284
Title: | Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice | Authors: | TERWEL, Dick Muyllaert, David DEWACHTER, Ilse Borghgraef, Peter Devijver, Herman Croes, Sophie Van Leuven, Fred |
Issue Date: | 2008 | Publisher: | AMER SOC INVESTIGATIVE PATHOLOGY, INC | Source: | The American journal of pathology, 172 (3) , p. 786 -798 | 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. | Keywords: | Glycogen-Synthase Kinase-3-Beta;Long-Term Potentiation;Transgenic Mice;Alzheimers-Disease;Tau-Protein;Neurofibrillary Tangles;Precursor Protein;Beta Peptides;A-Beta;Phosphorylation | Document URI: | http://hdl.handle.net/1942/30284 | DOI: | 10.2353/ajpath.2008.070904 | ISI #: | 000253616400022 | Rights: | American Society for Investigative Pathology | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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1-s2.0-S0002944010618408-main.pdf Restricted Access | Published version | 2 MB | Adobe PDF | View/Open Request a copy |
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