부산대학교 도서관

Assembly of monomeric amyloid β-protein (Aβ) into oligomeric structures is an important pathogenetic feature of Alzheimer's disease. The oligomer size distributions of aggregate-free, low molecular weight Aβ40 and Aβ42 can be assessed quantitatively using the technique of photo-induced cross-linking of unmodified proteins. This approach revealed that low molecular weight Aβ40 is a mixture of monomer, dimer, trimer, and tetramer, in rapid equilibrium, whereas low molecular weight Aβ42 preferentially exists as pentamer/hexamer units (paranuclei), which self-associate to form larger oligomers. Here, photo-induced cross-linking of unmodifled proteins was used to evaluate systematically the oligomerization of 34 physiologically relevant Aβ alloforms, including those containing familial Alzheimer's disease-linked amino acid substitutions, naturally occurring N-terminal truncations, and modifications altering the charge, the hydrophobicity, or the conformation of the peptide. The most important structural feature controlling early oligomerization was the length of the C terminus. Specifically, the side-chain of residue 41 in Aβ42 was important both for effective formation of paranuclei and for self-association of paranuclei into larger oligomers. The side-chain of residue 42, and the C-terminal carboxyl group, affected paranucleus selfassociation. Aβ40 oligomerization was particularly sensitive to substitutions of Glu[sup 22] or Asp[sup 23] and to truncation of the N terminus, but not to substitutions of Phe[sup 19] or Ala[sup 21]. Aβ42 oligomerization, in contrast, was largely unaffected by substitutions at positions 22 or 23 or by N-terminal truncations, but was affected significantly by substitutions of Phe[sup 19] or Ala[sup 21]. These results reveal how specific regions and residues control Aβ oligomerization and show that these controlling elements differ between Aβ40 and Aβ42. [ABSTRACT FROM AUTHOR]