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 (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.
Lambourne
Sarah L
SL
Neurobiology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom.
Sellers
Lynda A
LA
Bush
Toby G
TG
Choudhury
Shewly K
SK
Emson
Piers C
PC
Suh
Yoo-Hun
YH
Wilkinson
Lawrence S
LS
D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D016548:Prosencephalon / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012249:Rhombencephalon / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D019076:Transgenes; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D008565:Membrane Proteins; D016875:tau Proteins; D038341:Glycogen Synthase Kinases; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha