Interaction between Smad7 and beta-catenin is TGF-beta1 dependent and is associated with Abeta neurotoxicity: Implications for Alzheimer's disease

Alzheimer's disease (AD), also known as senile dementia is a neurodegenerative disorder. The AD brain is characterized by increased production and accumulation of the neurotoxic amyloid beta (Abeta) peptide. Abeta production is a result of proteolytic processing of amyloid precursor protein (APP) by beta and gamma-secretases. Mutations at the beta and gamma-secretase cleavage site of APP promote increased levels of Abeta. We used the familial Alzheimer's disease (FAD), TgCRND8 mice for our study. The TgCRND8 mouse expresses the mutant APP protein leading to plaque deposits within 3 months of age. Both, Wnt and Transforming growth factor (TGF)-beta1 signaling have been shown to be involved in AD progression. However, the mechanisms underlying the role of these pathways in AD are undefined. Western blotting and Immunohistochemistry showed that there was an increase in TGF-beta1, Smad7 and beta-catenin expression in TgCRND8 FAD samples relative to their controls. Immunostaining and immunoprecipitation of TgCRND8 brain samples showed increased nuclear co-localization, and interaction, respectively between Smad7 and beta-catenin. Increased DNA binding activity was observed in TgCRND8 using the TCF/LEF binding site. Nuclear co-localization of Smad7 and beta-catenin in TgCRND8 mice was associated with an increase in neuronal apoptosis, which was determined by the TUNEL assay. TGF-beta1 enhanced neuronal apoptosis in vitro by promoting Smad7 and beta-catenin interaction. Reduced Smad7 and beta-catenin expression by siRNA treatment lowered TGF-beta1 induced apoptosis. Interestingly, Abeta mediated an increase in TGF-beta1 expression. We also found that Smad7 and beta-catenin interaction due to TGF-beta1 treatment promoted the overexpression of c-myc, a pro-apoptotic protein. Thus, increased levels of TGF-beta1 are associated with neurodegeneration in AD, promoting the interaction between Smad7, beta-catenin and LEF-1, and accumulation in the nucleus. As a result, a target of Wnt signaling, c-myc is expressed promoting neuronal apoptosis.