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- W2009761443 abstract "Hyperphosphorylation and formation of insoluble aggregates of tau are common features of all human tauopathies. The relative importance of phosphorylation at each of the many known sites in tau remains unclear. At 5-6 months of age homozygous P301S mice develop a neurological phenotype characterized by general muscle weakness, tremor and severe paraparesis. In this study we characterized the temporal changes in tau conformational and phosphorylation status in P301S mice to determine which post-translational modifications of tau best predict decline in motor function. Homozygous P301S mice were generated as previously described (Allen et al, J. Neurosci. (2002)). Phosphorylation and conformational status of tau in multiple brain and spinal cord regions in each age group was quantified using a panel of proprietary Alphascreen assays and by standard IHC methods. In young 1 month old P301S mice phosphorylation of tau on several epitopes, notably those found on normal soluble tau and including pS202 and pS396/pS404, was already relatively high, similar to that measured in control 1 month old C57/Blk6 mice. Phosphorylation status of these epitopes in P301S mice was relatively unchanged as animals matured to 3 and 5 months of age and remained similar to that seen in control, age-matched mice. By contrast, in young 1 month old P301S mice the phosphorylation of tau on epitopes predominantly associated with aggregated, insoluble tau such as AT8 (both pS202 and pT205) and pS409 was very low, but increased dramatically as the animals reached 5 months of age. The amount of tau in an altered conformational state, as measured using MC-1 and TG3 antibodies, was also dramatically increased in older P301S mice, particularly in the brain stem and spinal cord. The level of phosphorylation of tau on epitopes that are already highly phosphorylated in normal, soluble tau does not change significantly as P301S mice age and their motor function declines. Conversely, phosphorylation at both pT205 and pS409 and conformational change in tau increases dramatically as P301S mice reach 5 months of age and are highly correlated with the decline in motor function seen in these older animals." @default.
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- W2009761443 date "2010-07-01" @default.
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- W2009761443 title "P1-348: Dramatic increases in phosphorylation of tau only on specific epitopes correlates with decline in motor function in aged P301S mice" @default.
- W2009761443 doi "https://doi.org/10.1016/j.jalz.2010.05.901" @default.
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