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A Direct Interaction between Transforming Growth Factor (TGF)-βs and Amyloid-β Protein Affects Fibrillogenesis in a TGF-βReceptor-independent Manner
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 TG...
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Published in: | The Journal of biological chemistry 2003-10, Vol.278 (40), p.38715 |
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Main Authors: | , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | 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-(1â40), in this model suggesting that there may be a direct, receptor-independent interaction between TGF-β
and Aβ-(1â40). Surface plasmon resonance confirmed that TGF-β binds with high affinity directly to Aβ-(1â40) and electron
microscopy revealed that TGF-β enhances Aβ-(1â40) 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. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M304080200 |