A Direct Interaction between Transforming Growth Factor (TGF)-βs and Amyloid-β Protein Affects Fibrillogenesis in a TGF-β Receptor-independent Manner

From National Research Council Canada

DOIResolve DOI: https://doi.org/10.1074/jbc.M304080200
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Name affiliation
  1. National Research Council of Canada. NRC Biotechnology Research Institute
FormatText, Article
Journal titleThe Journal of Biological Chemistry
ISSN0021-9258
1083-351X
Volume278
Issue40
Pages38715–38722
Subjectpharmaceutical
Abstract
Transforming growth factor-β (TGF-β) receptor-mediated signaling has been proposed to mediate both the beneficial and deleterious roles for this cytokine in amyloid-β protein (Aβ) function. In order to assess receptor dependence of these events, we used PC12 cell cultures, which are devoid of TGF-β receptors. Surprisingly, TGF-β potentiated the neurotoxic effects of the 40-residue Aβ peptide, Aβ-(1–40), in this model suggesting that there may be a direct, receptor-independent interaction between TGF-β and Aβ-(1–40). Surface plasmon resonance confirmed that TGF-β binds with high affinity directly to Aβ-(1–40) and electron microscopy revealed that TGF-β enhances Aβ-(1–40) oligomerization. Immunohistochemical examination of mouse brain revealed that hippocampal CA1 and dentate gyrus, two regions classically associated with Aβ-mediated pathology, lack TGF-β Type I receptor immunoreactivity, thus indicating that TGF-β 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-β, but also help to reconcile the literature interpreting the role of TGF-β in Aβ function. These data support a critical etiological role for this mechanism in neuropathological amyloidoses.
Publication date
PublisherAmerican Society for Biochemistry and Molecular Biology
LanguageEnglish
Peer reviewedYes
NRC numberNRC-BRI-46165
NPARC number3540136
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Record created2009-03-01
Record modified2020-04-02
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