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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
Authors
Lambourne, Sarah L.; Sellers, Lynda A.; Bush, Toby G.; Choudhury, Shewly K.; Emson, Piers C.; Suh, Yoo-Hun; Wilkinson, Lawrence S.
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 Hybridization*MAP Kinase Signaling SystemMembrane Proteins/chemistryMiceMice, TransgenicMutationPhosphorylationProsencephalon/metabolismProtein Structure, TertiaryRhombencephalon/metabolismSignal TransductionTime FactorsTransgenestau Proteins/*chemistry/metabolism
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

http://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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