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A direct interaction between transforming growth factor (TGF)-betas and amyloid-beta protein affects fibrillogenesis in a TGF-beta receptor-independent manner.

  • Author(s): Mousseau, Darrell D
  • Chapelsky, Sarah
  • De Crescenzo, Gregory
  • Kirkitadze, Marina D
  • Magoon, Joanne
  • Inoue, Sadayuki
  • Teplow, David B
  • O'Connor-McCourt, Maureen D
  • et al.
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.

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