TY - JOUR
T1 - Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice
AU - Ishizawa, Takashi
AU - Sahara, Narahiko
AU - Ishiguro, Koichi
AU - Kersh, Jay
AU - McGowan, Eileen
AU - Lewis, Jada
AU - Hutton, Michael
AU - Dickson, Dennis W.
AU - Yen, Shu Hui
N1 - Funding Information:
This study was partially supported by the Chinese National Natural Sciences Foundation Key Project (39730310), the Chinese National Key Project of Basic Research, the Chinese High-tech Program, and the Chinese National Distinguished Young Scientist Award (39625014). The authors thank Professor Bai Lu and Professor Yuanmin Li for critical suggestions and Ms. Jinghong Wan for help with image analysis.
PY - 2003/9/1
Y1 - 2003/9/1
N2 - Transgenic mice expressing human tau with P301L missense mutation (JNPL3) develop progressive amyotrophy, neurofibrillary degeneration, and neuronal loss. Mating of JNPL3 with transgenic mice expressing mutant amyloid precursor protein (Tg2576) leads to bigenic (TAPP) mice with enhanced neurofibrillary pathology. TAPP and JNPL3 mice were studied with immunocytochemistry and immunoblotting with antibodies to glycogen synthase kinase-3 (GKS3) to determine whether the development of tauopathy is associated with activation or increased expression of GSK3, and when the observed changes occur with respect to neurofibrillary tangle (NFT) formation. Accumulation of GSK3α/β phosphorylated at Y279/216 was observed in neurons containing NFTs and granulovacuolar degeneration (GVD), but not in normal neurons or neurons with pretangles. More GSK3 immunoreactive NFTs were detected in TAPP than JNPL3 mice, especially in the amygdala. These differences were notable only in old animals. There was no significant difference between animals with and without NFTs in the level of total, inactive, or Y216-phosphorylated (pY216)GSK3β. No apparent GSK3 accumulation was detected in neurons in Tg2576 mice. There was also no significant difference in the distribution of GSK3 in lysates fractionated based on their solubility in various reagents, including the sarkosyl-insoluble fraction. The results suggest that the pY216 GSK3β accumulates in NFT and GVD due to redistribution rather than increased expression or activation, and that pre-existence of tau abnormalities is required for APP/Aβ to exert their effects on tau pathology in TAPP mice.
AB - Transgenic mice expressing human tau with P301L missense mutation (JNPL3) develop progressive amyotrophy, neurofibrillary degeneration, and neuronal loss. Mating of JNPL3 with transgenic mice expressing mutant amyloid precursor protein (Tg2576) leads to bigenic (TAPP) mice with enhanced neurofibrillary pathology. TAPP and JNPL3 mice were studied with immunocytochemistry and immunoblotting with antibodies to glycogen synthase kinase-3 (GKS3) to determine whether the development of tauopathy is associated with activation or increased expression of GSK3, and when the observed changes occur with respect to neurofibrillary tangle (NFT) formation. Accumulation of GSK3α/β phosphorylated at Y279/216 was observed in neurons containing NFTs and granulovacuolar degeneration (GVD), but not in normal neurons or neurons with pretangles. More GSK3 immunoreactive NFTs were detected in TAPP than JNPL3 mice, especially in the amygdala. These differences were notable only in old animals. There was no significant difference between animals with and without NFTs in the level of total, inactive, or Y216-phosphorylated (pY216)GSK3β. No apparent GSK3 accumulation was detected in neurons in Tg2576 mice. There was also no significant difference in the distribution of GSK3 in lysates fractionated based on their solubility in various reagents, including the sarkosyl-insoluble fraction. The results suggest that the pY216 GSK3β accumulates in NFT and GVD due to redistribution rather than increased expression or activation, and that pre-existence of tau abnormalities is required for APP/Aβ to exert their effects on tau pathology in TAPP mice.
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U2 - 10.1016/S0002-9440(10)63465-7
DO - 10.1016/S0002-9440(10)63465-7
M3 - Article
C2 - 12937146
AN - SCOPUS:0042425738
SN - 0002-9440
VL - 163
SP - 1057
EP - 1067
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -