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Molecular and Cellular Biology, January 2005, p. 278-293, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.278-293.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Neurobiology Programme, The Babraham Institute, Babraham, Cambridge, United Kingdom,¹ Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, South Korea²

Received 9 June 2004/ Returned for modification 21 June 2004/ Accepted 6 September 2004

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 (tau_V337M) 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 tau_V337M and the familial amyloid precursor protein AD mutation APP_V717I in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to "single" tau_V337M 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-3ß or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APP_V717I-CT100 transgene expression as near identical changes were observed in single APP_V717I-CT100 mice. Age-dependent deficits in memory were also associated with tau_V337M and APP_V717I-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.

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