title: Aβ association inhibition by transferrin.
abstract: The iron-transport glycoprotein transferrin has recently been shown to serve as a potent inhibitor of Aβ self-association. Although this novel, to our knowledge, inhibitory function of transferrin is of potential therapeutic interest for the treatment of Alzheimer's disease, the underlying mechanism is still not fully understood. Although it has been shown that the Fe(III) sequestration by transferrin reduces oxidative damage and Aβ aggregation, it is not clear whether transferrin is also able to inhibit Aβ self-association through direct binding of Aβ. Here, using saturation transfer and off-resonance relaxation NMR spectroscopy, we show that transferrin inhibits Aβ aggregation also by preferentially binding Aβ oligomers and outcompeting Aβ monomers that would otherwise cause the growth of the Aβ oligomers into larger assemblies. This inhibitory mechanism is different from the iron-sequestration model, but it is qualitatively similar to a mechanism previously proposed for the inhibition of Aβ self-association by another plasma and cerebrospinal fluid protein, i.e., human serum albumin. These results suggest that Aβ monomer competition through direct Aβ oligomer binding might be a general strategy adopted by proteins in plasma and cerebrospinal fluid to prevent Aβ aggregation.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, L8S 4M1, Canada.
authors.forename: Annie V
authors.initials: AV
authors.lastname: Raditsis
authors.forename: Julijana
authors.initials: J
authors.lastname: Milojevic
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Melacini
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism*; D058105:Polymerization / Q000187:drug effects; D011485:Protein Binding; D014168:Transferrin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D014168:Transferrin; C092395:amyloid beta-protein (12-28)
keywords: AD; Alzheimer’s disease; CNS; CSF; HSA; ICP; ORR; SL; STD; STR; Tf; WG; central nervous system; cerebrospinal fluid; human serum albumin; inductively coupled plasma; off-resonance relaxation; saturation transfer difference; saturation transfer reference; spin-lock; transferrin; watergate water-suppression NMR technique