Overexpression of GSK3betaS9A resulted in tau hyperphosphorylation and morphology reminiscent of pretangle-like neurons in the brain of PDGSK3beta transgenic mice.
It has been demonstrated that GSK3beta is involved in Alzheimer Disease (AD) pathogenesis. In order to understand the underlying mechanism, we have generated and characterized transgenic mice in which the constitutively active human GSK3beta (with S9A mutation) was overexpressed in the brain under the control of the platelet-derived growth factor (PDGF) B-chain promoter. Varying levels of human GSK3betaS9A transgene protein expression was observed in six of the seven founders generated. Line 3083, 3107, 3112 and 3125 displayed higher GSK3betaS9A protein expression levels. Immunostaining analysis demonstrated that transgene expression was observed mainly in cortex and hippocampus of transgenic brain. Expression of human GSK3beta transgene did not significantly change the brain total GSK3beta protein levels in any of the generated mouse lines, as comparing to age matched wild type mice. Although significant kinase activity was detected in human GSK3betaS9A transgene protein extracted from brains of all six expressing lines, significant increase in total GSK3betaS9A kinase activity was observed only in the offspring of line 3083 and 3107. By analyzing the offspring from several transgenic mouse lines, including lines other than 3083 and 3107, it was found that overexpressed constitutively active human GSK3betaS9A resulted in hyperphosphorylation of tau and morphology reminiscent of pretangle-like neurons in cortex and hippocampus.
Li
Baolin
B
Lilly Research Laboratories, Eli Lilly and company, Lilly corporate center, Drop code 0510, Indianapolis, Indiana 46285, USA. Li_Baolin@Lilly.com
Ryder
John
J
Su
Yuan
Y
Moore
Steven A
SA
Liu
Feng
F
Solenberg
Patricia
P
Brune
Kellie
K
Fox
Niles
N
Ni
Binhui
B
Liu
Rugao
R
Zhou
Yan
Y
D019943:Amino Acid Substitution; D000818:Animals; D000077214:Becaplermin; D001921:Brain / Q000201:enzymology / Q000473:pathology*; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016875:tau Proteins; D000077214:Becaplermin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3