G272V, P301L, R406W
Tau Immunoreactivity Observed
12E8, AT8, AT270, PHF1, PHF6, T3P AT8, AT270, PHF1, PHF6, T3P MC-1
ALZ50, AT8, AT180, AT270, MCI, PHF1
ALZ50, AT8, AT100, AT180, CP3, CP9, CP13, MCI, PHF1
AD199, AT8, AT180, MCI, TG3
PHF1 12E8, AD2, AT8.TG3 ALZ50, AT8, PS199 ALZ50, AT180, PS199, PS404 AT8, AT180
of neurofibrillary pathology (11). In a separate study, Ahlijanian and coworkers (12) overexpressed p25, a calpain cleavage product of p35, the endogenous regulator of another potential tau kinase, cdk5 (13). P25 lacks the regulatory region of p35 and thus causes constitutive activation of cdk5. P25 production has been suggested to underlie tau hyperphosphorylation in AD (13). Mice expressing p25 developed hyperphosphorylated tau and silver-positive inclusions that also had neurofilament immunoreactivity, but again neurofibrillary pathology was not observed (12). Bian and colleagues (14) recently generated another transgenic mouse line, which overexpressed p25 in neurons. Despite the elevated cdk5 activity observed in these animals, axonal degeneration resulted in the absence of neurofibrillary tau pathology.
Kins and colleagues (15) addressed the role of tau hyperphosphorylation by generating mice that expressed a dominant negative mutant of the catalytic subunit of protein phosphatase 2A transgene in neurons. Abnormal tau phosphorylation (AT8 immunoreactivity) was observed in Purkinje cells of these transgenic mice. Ubiquitin immunoreactivity colocalized with the AT8 immunopositive aggregates; however, neurofibrillary lesions were not identified.
Transgenesis that resulted in altered tau kinase or phosphatase activity has produced some of the initial features of the tau pathology seen in human disease; however, the absence of neurofibrillary pathology or pronounced cell loss suggests that these enzymes may not initiate mature tau pathology. These models have now been bred with various tau transgenic models to further define the role that altered kinase or phosphatase activity has in the presence of early and late tau pathology.
Was this article helpful?