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Title: Amyloid Activates GSK-3beta to Aggravate Neuronal Tauopathy in Bigenic Mice
Authors: Terwel, Dick *
Muyllaert, David *
Dewachter, Ilse *
Borghgraef, Peter
Croes, Sophie
Devijver, Herman
Van Leuven, Freddy # ×
Issue Date: Mar-2008
Series Title: American Journal of Pathology vol:172 issue:3 pages: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.
ISSN: 0002-9440
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Experimental Genetics and Transgenesis (-)
Associated Laboratories - miscellaneous (-)
Department of Human Genetics - miscellaneous
* (joint) first author
× corresponding author
# (joint) last author

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