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P3‐199: Intrinsically disordered protein tau with unsheltered microtubule‐binding domain become mis‐disordered: Implications for neurofibrillary degeneration
Author(s) -
Skrabana Rostislav,
Bartkova Miriam,
Kovacech Branislav,
Hanes Jozef,
Novak Michal
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.1073
Subject(s) - intrinsically disordered proteins , neurodegeneration , tau protein , tauopathy , chemistry , microtubule , microbiology and biotechnology , biophysics , biology , biochemistry , alzheimer's disease , medicine , disease , pathology
Background: rTg4510 is a conditional mouse model of tauopathy that expresses mutant human tau within the mouse forebrain at 13 fold that of endogenous tau. Cognitive impairment and pre-tangle pathology within the forebrain is observed at 2.5 months. Mature tangle pathology is apparent by 4 months of age in the cortex and 5.5 months in the CA1, accompanied by significant neuronal loss. Inhibiting transgenic tau expression via doxycycline (dox) administration can reduce the cognitive deficits in rTg4510 mice. Methods: The rTg4510 inducible tau model has well-defined biochemical, pathological, and phenotypic stages, and we have now exploited this model to determine if aged neurons are predisposed to tauopathy. To explore this question, we administered dox to mothers from conception of rTg4510 litters and continued to dox weaned rTg4510 mice and controls until key pathological time points as defined in rTg4510 mice who did not receive dox (ON). In the first cohort, we aged rTg4510 mice to 2.75 months before inducing tau expression for the subsequent 2.75 months (2.75OFF/ 2.75ON mice). For the second cohort, we aged rTg4510 mice to 5.5 months before inducing tau expression for the subsequent 2.75 months (5.5OFF/ 2.75ON mice). Finally, in the third cohort, we aged rTg4510 mice to 5.5 months before inducing tau expression for an additional 5.5 months (5.5OFF/5.5ON mice). ON rTg4510 mice, rTg4510 mice continually receiving dox (OFF), and non-transgenic mice at 2.75, 5.5, 8.25, and 11 months of age were compared to the three experimental cohorts with biochemical and neuropathological measures of tauopathy. Results: rTg4510 mice in which transgenic tau expression was induced at key biochemical time points showed reduction in tau hyperphosphorylation and accumulation of the 64kD species of sarkosyl insoluble tau when compared to rTg4510 (ON) mice. Additionally, ultrastructural analysis of the sarkosyl insoluble fraction of tau from OFF/ON mice suggests the presence of amorphous, ill-defined clumps of tau protein compared to defined tau filaments in rTg4510 ON mice. Neuropathological analyses are still ongoing. Conclusions: This data clearly shows that the age of a neuron, alone, does not predispose neurons to rapid induction of tauopathy.