Kinase activities increase during the development of tauopathy in htau mice.
Hyperphosphorylated tau aggregates are the core constituent of neurofibrillary tangles. Recent research has shown a division between the presence of tangles, neurodegeneration and subsequent memory impairment, raising the possibility that an earlier pre-aggregated form of tau may be toxic. To gain further insight into the relationship between abnormal forms of tau, we have analyzed pathological changes in tau during tauopathy development in tangle-forming transgenic mice. In addition, we have quantified changes in the endogenous levels of a panel of protein kinases. We show progressive increases in aggregated tau and disease-specific conformational change, with hyperphosphorylation occurring in an age-dependent manner at specific sites. There were significant correlations between specific phosphorylation changes and amounts of aggregated tau and and abnormal tau conformations. Of the protein kinases tested, we found increases in phosphorylated (activated) p38 and the cyclin-dependent kinase-5 neuronal activators, p35 and p25, with aging, in the htau line, but not in non-tangle-forming control mice. Changes in tau kinases correlated with the amount of tau present in abnormal conformations and with insoluble tau in htau mice. These data suggest that cdk5 and p38 may be associated with pathological changes in wild-type human tau during the progressive development of tauopathy.
Kelleher
Ian
I
King's College London, Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, De Crespigny Park, London, UK.
Garwood
Claire
C
Hanger
Diane P
DP
Anderton
Brian H
BH
Noble
Wendy
W
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D010770:Phosphotransferases; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism*; D024801:Tauopathies / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D015854:Up-Regulation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
C492236:Cdk5r1 protein, mouse; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D010770:Phosphotransferases; D011494:Protein Kinases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases