Understanding the molecular basis for the inhibition of the Alzheimer's Abeta-peptide oligomerization by human serum albumin using saturation transfer difference and off-resonance relaxation NMR spectroscopy.
Human serum albumin (HSA) inhibits the formation of amyloid beta-peptide (Abeta) fibrils in human plasma. However, currently it is not known how HSA affects the formation of the highly toxic soluble diffusible oligomers that occur in the initial stages of Abeta fibrillization. We have therefore investigated by solution NMR the interaction of HSA with the Abeta(12-28) peptide, which has been previously shown to provide a reliable and stable model for the early prefibrillar oligomers as well as to contain key determinants for the recognition by albumin. For this purpose we propose a novel NMR approach based on the comparative analysis of Abeta in its inhibited and filtrated states monitored through both saturation transfer difference and recently developed nonselective off-resonance relaxation experiments. This combined NMR strategy reveals a mechanism for the oligomerization inhibitory function of HSA, according to which HSA targets preferentially the soluble oligomers of Abeta(12-28) rather than its monomeric state. Specifically, HSA caps the exposed hydrophobic patches located at the growing and/or transiently exposed sites of the Abeta oligomers, thereby blocking the addition of further monomers and the growth of the prefibrillar assemblies. The proposed model has implications not only for the pharmacological treatment of Alzheimer's disease specifically but also for the inhibition of oligomerization in amyloid-related diseases in general. In addition, the proposed NMR approach is expected to be useful for the investigation of the mechanism of action of other oligomerization inhibitors as well as of other amyloidogenic systems.
Milojevic
Julijana
J
Department of Chemistry, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada.
Esposito
Veronica
V
Das
Rahul
R
Melacini
Giuseppe
G
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D005374:Filtration; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D008970:Molecular Weight; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism*; D017186:Titrimetry
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012709:Serum Albumin; C092395:amyloid beta-protein (12-28)