S-Space College of Medicine/School of Medicine (의과대학/대학원) Pharmacology (약리학전공) Journal Papers (저널논문_약리학전공)
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
- Issue Date
- American Society for Microbiology
- Mol. Cell Biol. 25:278-293
- Alzheimer Disease/genetics ; Amyloid beta-Protein/metabolism ; Animals ; Blotting, Western ; Brain/metabolism ; Cell Membrane/metabolism ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases/metabolism ; DNA, Complementary/metabolism ; Enzyme-Linked Immunosorbent Assay ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinases/metabolism ; Humans ; Image Processing, Computer-Assisted ; Immunohistochemistry ; In Situ Hybridization ; Membrane Proteins/chemistry ; Mice ; Mice, Transgenic ; Mutation ; Phosphorylation ; Prosencephalon/metabolism ; Protein Structure, Tertiary ; Rhombencephalon/metabolism ; Signal Transduction ; Time Factors ; Transgenes ; tau Proteins/*chemistry/metabolism ; MAP Kinase Signaling System
- 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 NH(2)-terminal kinase) but not glycogen synthase kinase-3alphabeta 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.
- 0270-7306 (Print)
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