1. A direct interaction between transforming growth factor (TGF)-betas and amyloid-beta protein affects fibrillogenesis in a TGF-beta receptor-independent manner.
- Author
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Mousseau DD, Chapelsky S, De Crescenzo G, Kirkitadze MD, Magoon J, Inoue S, Teplow DB, and O'Connor-McCourt MD
- Subjects
- Animals, Binding, Competitive, Cell Line, Circular Dichroism, Densitometry, Female, Hippocampus metabolism, Immunohistochemistry, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Microscopy, Electron, Neurons metabolism, PC12 Cells, Protein Binding, Protein Isoforms, Rats, Receptors, Transforming Growth Factor beta metabolism, Signal Transduction, Surface Plasmon Resonance, Time Factors, Amyloid beta-Peptides metabolism, Peptide Fragments metabolism, Transforming Growth Factor beta metabolism
- Abstract
Transforming growth factor-beta (TGF-beta) receptor-mediated signaling has been proposed to mediate both the beneficial and deleterious roles for this cytokine in amyloid-beta protein (Abeta) function. In order to assess receptor dependence of these events, we used PC12 cell cultures, which are devoid of TGF-beta receptors. Surprisingly, TGF-beta potentiated the neurotoxic effects of the 40-residue Abeta peptide, Abeta-(1-40), in this model suggesting that there may be a direct, receptor-independent interaction between TGF-beta and Abeta-(1-40). Surface plasmon resonance confirmed that TGF-beta binds with high affinity directly to Abeta-(1-40) and electron microscopy revealed that TGF-beta enhances Abeta-(1-40) oligomerization. Immunohistochemical examination of mouse brain revealed that hippocampal CA1 and dentate gyrus, two regions classically associated with Abeta-mediated pathology, lack TGF-beta Type I receptor immunoreactivity, thus indicating that TGF-beta receptor-mediated signaling would not be favored in these regions. Our observations not only provide for a unique, receptor-independent mechanism of action for TGF-beta, but also help to reconcile the literature interpreting the role of TGF-beta in Abeta function. These data support a critical etiological role for this mechanism in neuropathological amyloidoses.
- Published
- 2003
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