Tau overexpression in transgenic mice induces glycogen synthase kinase 3beta and beta-catenin phosphorylation.
The abnormal phosphorylations of tau, GSK3beta, and beta-catenin have been shown to perform a crucial function in the neuropathology of Alzheimer's disease (AD). The primary objective of the current study was to determine the manner in which overexpressed htau23 interacts and regulates the behavior and phosphorylation characteristics of tau, GSK3beta, and beta-catenin. In order to accomplish this, transgenic mice expressing neuron-specific enolase (NSE)-controlled human wild-type tau (NSE/htau23) were created. Transgenic mice evidenced the following: (i) tendency toward memory impairments at later stages, (ii) dramatic overexpression of the tau transgene, coupled with increased tau phosphorylation and paired helical filaments (PHFs), (iii) high levels of GSK3beta phosphorylation with advanced age, resulting in increases in the phosphorylations of tau and beta-catenin, (iv) an inhibitory effect of lithium on the phosphorylations of tau, GSK3beta, and beta-catenin, but not in the non-transgenic littermate group. Therefore, the overexpression of NSE/htau23 in the brains of transgenic mice induces abnormal phosphorylations of tau, GSK3beta, and beta-catenin, which are ultimately linked to neuronal degeneration in cases of AD. These transgenic mice are expected to prove useful for the development of new drugs for the treatment of AD.
Shim
S B
SB
Division of Laboratory Animal Resources, Korea FDA, National Institute of Toxicological Research, 5 Nokbun-dong Eunpyung-ku, Seoul 122-704, Korea.
Lim
H J
HJ
Chae
K R
KR
Kim
C K
CK
Hwang
D Y
DY
Jee
S W
SW
Lee
S H
SH
Sin
J S
JS
Leem
Y H
YH
Lee
S H
SH
Cho
J S
JS
Lee
H H
HH
Choi
S Y
SY
Kim
Y K
YK
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D004924:Escape Reaction / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D013550:Swimming; D051176:beta Catenin / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D051176:beta Catenin; D016875:tau Proteins; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D010751:Phosphopyruvate Hydratase