TGF-beta1 is increased in a transgenic mouse model of familial Alzheimer's disease and causes neuronal apoptosis.
Alzheimer's disease (AD) is a neurodegenerative disorder, due to excess amyloid-beta peptide (Abeta). TGF-beta1 and beta-catenin signaling pathways have been separately implicated in modulating Abeta-neurotoxicity. However, the underlying mechanisms remain unclear. Here, we report that TGF-beta1 and nuclear Smad7 and beta-catenin levels were markedly upregulated in cortical brain regions of the TgCRND8 mice, a mouse model of familial Alzheimer's disease. Coimmunoprecipitation of cortical brain tissue lysates revealed an interaction between Smad7 and beta-catenin. This interaction which was significantly enhanced in the TgCRND8 mice was also associated with an increase in TCF/LEF DNA-shift binding activity. TCF/LEF reporter gene activity was significantly increased in mouse primary cortical neuronal cultures (MCN) from the TgCRND8 mice, compared to controls. Interestingly, exposure of MCN to Abeta(1-42) led to an increase in TGF-beta1 and nuclear levels of both beta-catenin and Smad7. Furthermore, addition of TGF-beta1 to the MCN caused an increase in apoptosis and Smad7 levels. When Smad7 or beta-catenin levels were reduced by siRNA, TGF-beta1-induced apoptosis was suppressed, indicating that both Smad7 and beta-catenin are required for TGF-beta1-induced neurotoxicity. Since Abeta(1-42)-induced TGF-beta1, we suggest that TGF-beta1 may amplify Abeta(1-42)-mediated neurodegeneration in AD via Smad7 and beta-catenin interaction and nuclear localization.
Department of Biochemistry and Medical Genetics, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, MB R3E 0W3 Canada.
Pradeep
P
Salins
Yang
Y
He
Kelly
K
Olson
Gordon
G
Glazner
Tarek
T
Kashour
Francis
F
Amara
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051906:Smad7 Protein / Q000378:metabolism; D051820:TCF Transcription Factors / Q000235:genetics; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D016229:Amyloid beta-Peptides; C495267:CTNNB1 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D051820:TCF Transcription Factors; D053773:Transforming Growth Factor beta1; D051176:beta Catenin