A direct interaction between transforming growth factor (TGF)-betas and amyloid-beta protein affects fibrillogenesis in a TGF-beta receptor-independent manner.
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.
Mousseau
Darrell D
DD
Cell Signaling Group, Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon S7N 5E4, Canada. darrell.mousseau@usask.ca
Chapelsky
Sarah
S
De Crescenzo
Gregory
G
Kirkitadze
Marina D
MD
Magoon
Joanne
J
Inoue
Sadayuki
S
Teplow
David B
DB
O'Connor-McCourt
Maureen D
MD
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002942:Circular Dichroism; D003720:Densitometry; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C078592:amyloid beta-protein (1-40)