Increased tau Phosphorylation on Mitogen-Activated Protein Kinase Consensus Sites and Cognitive Decline in Transgenic Models for Alzheimer's Disease and FTDP-17: Evidence for Distinct Molecular Processes Underlying tau Abnormalities
Abnormal tau phosphorylation occurs in several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here, we compare mechanisms of tau phosphorylation in mouse models of FTDP-17 and AD. Mice expressing a mutated form of human tau associated with FTDP-17 (tauV337M) showed age-related increases in exogenous tau phosphorylation in the absence of increased activation status of a number of kinases known to phosphorylate tau in vitro. In a “combined” model, expressing both tauV337M and the familial amyloid precursor protein AD mutation APPV717I in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to “single” tauV337M mice. These effects were concomitant with increased activation status of mitogen-activated protein kinase (MAPK) family members (extracellular regulated kinases 1 and 2, p38, and c-Jun NH2-terminal kinase) but not glycogen synthase kinase-3αβ or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APPV717I-CT100 transgene expression as near identical changes were observed in single APPV717I-CT100 mice. Age-dependent deficits in memory were also associated with tauV337M and APPV717I-CT100 expression. The data reveal distinct routes to abnormal tau phosphorylation in models of AD and FTDP-17 and suggest that in AD, tau irregularities may be linked to processing of APP C-terminal fragments via specific effects on MAPK activation status.