| First Author | Liao MC | Year | 2010 |
| Journal | J Biol Chem | Volume | 285 |
| Issue | 46 | Pages | 35590-8 |
| PubMed ID | 20807757 | Mgi Jnum | J:166874 |
| Mgi Id | MGI:4849910 | Doi | 10.1074/jbc.M110.169599 |
| Citation | Liao MC, et al. (2010) N-terminal domain of myelin basic protein inhibits amyloid beta-protein fibril assembly. J Biol Chem 285(46):35590-8 |
| abstractText | Accumulation of amyloid beta-protein (Abeta) into brain parenchymal plaques and the cerebral vasculature is a pathological feature of Alzheimer disease and related disorders. Abeta peptides readily form beta-sheet-containing oligomers and fibrils. Previously, we reported a strong interaction between myelin basic protein (MBP) and Abeta peptides that resulted in potent inhibition of fibril assembly (Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2007) J. Biol. Chem. 282, 9952-9961; Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2009) Biochemistry 48, 4720-4727). MBP is recognized as a highly post-translationally modified protein. In the present study, we demonstrate that human MBP purified from either brain or a bacterial recombinant expression system comparably bound to Abeta and inhibited Abeta fibril assembly indicating that post-translational modifications are not required for this activity. We also show that purified mouse brain MBP and recombinantly expressed mouse MBP similarly inhibited Abeta fibril formation. Through a combination of biochemical and ultrastructural techniques, we demonstrate that the binding site for Abeta is located in the N-terminal 64 amino acids of MBP and that a stable peptide (MBP1) comprising these residues was sufficient to inhibit Abeta fibrillogenesis. Under conditions comparable with those used for Abeta, the fibrillar assembly of amylin, another amyloidogenic peptide, was not inhibited by MBP1, although MBP1 still bound to it. This observation suggests that the potent inhibitory effect of MBP on fibril formation is not general to amyloidogenic peptides. Finally, MBP1 could prevent the cytotoxic effects of Abeta in primary cortical neurons. Our findings suggest that inhibition of Abeta fibril assembly by MBP, mediated through its N-terminal domain, could play a role in influencing amyloid formation in Alzheimer disease brain and corresponding mouse models. |
