Cell-cycle markers in a transgenic mouse model of human tauopathy: increased levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1.
Recent evidence has suggested that an abnormal reactivation of the cell cycle may precede and cause the hyperphosphorylation and filament formation of tau protein in Alzheimer's disease and other tauopathies. Here we have analyzed the expression and/or activation of proteins involved in cell-cycle progression in the brain and spinal cord of mice transgenic for mutant human P301S tau protein. This mouse line recapitulates the essential molecular and cellular features of the human tauopathies, including hyperphosphorylation and filament formation of tau protein. None of the activators and co-activators of the cell cycle tested were overexpressed or activated in 5-month-old transgenic mice when compared to controls. By contrast, the levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 were increased in brain and spinal cord of transgenic mice. Both inhibitors accumulated in the cytoplasm of nerve cells, the majority of which contained inclusions made of hyperphosphorylated tau protein. A similar staining pattern for p21Cip1 and p27Kip1 was also present in the frontal cortex from a case of FTDP-17 with the P301L tau mutation. Thus, reactivation of the cell cycle was not involved in tau hyperphos-phorylation and filament formation, consistent with expression of p21Cip1 and p27Kip1 in tangle-bearing nerve cells.
Delobel
Patrice
P
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Lavenir
Isabelle
I
Ghetti
Bernardino
B
Holzer
Max
M
Goedert
Michel
M
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000032:analysis / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000737:chemistry; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D016875:tau Proteins / Q000235:genetics
D015415:Biomarkers; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27