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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

Cited 39 time in Web of Science Cited 38 time in Scopus
Issue Date
2005
Publisher
American Society for Microbiology
Citation
Mol. Cell Biol. 25:278-293
Keywords
Alzheimer Disease/geneticsAmyloid beta-Protein/metabolismAnimalsBlotting, WesternBrain/metabolismCell Membrane/metabolismCyclin-Dependent Kinase 5Cyclin-Dependent Kinases/metabolismDNA, Complementary/metabolismEnzyme-Linked Immunosorbent AssayGlycogen Synthase Kinase 3/metabolismGlycogen Synthase Kinases/metabolismHumansImage Processing, Computer-AssistedImmunohistochemistryIn Situ HybridizationMembrane Proteins/chemistryMiceMice, TransgenicMutationPhosphorylationProsencephalon/metabolismProtein Structure, TertiaryRhombencephalon/metabolismSignal TransductionTime FactorsTransgenestau Proteins/*chemistry/metabolismMAP Kinase Signaling System
Abstract
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.
ISSN
0270-7306 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15601849

https://hdl.handle.net/10371/28239
DOI
https://doi.org/10.1128/MCB.25.1.278-293.2005
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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