Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice.
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 GSK3alpha/beta 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)GSK3beta. 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 GSK3beta 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/Abeta to exert their effects on tau pathology in TAPP mice.
Ishizawa
Takashi
T
Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32225, USA.
Sahara
Narahiko
N
Ishiguro
Koichi
K
Kersh
Jay
J
McGowan
Eileen
E
Lewis
Jada
J
Hutton
Michael
M
Dickson
Dennis W
DW
Yen
Shu-Hui
SH
D000818:Animals; D001921:Brain / Q000378:metabolism; D005591:Chemical Fractionation; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis / Q000378:metabolism*; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D010766:Phosphorylation; D013116:Spinal Cord / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors; D014018:Tissue Distribution; D014020:Tissue Extracts / Q000737:chemistry; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D014020:Tissue Extracts; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3