Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice

Takashi Ishizawa, Narahiko Sahara, Koichi Ishiguro, Jay Kersh, Eileen McGowan, Jada Lewis, Michael Hutton, Dennis W. Dickson, Shu Hui Yen

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1057-1067
Number of pages11
JournalAmerican Journal of Pathology
Volume163
Issue number3
DOIs
StatePublished - Sep 1 2003

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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