The N‐terminal region of non‐Aβ component of Alzheimer's Disease amyloid is responsible for its tendency to assume β‐sheet and aggregate to form fibrils

Examination of the N‐terminal sequence of non‐Aβ component of Alzheimer's Disease amyloid (NAC) revealed a degree of similarity to regions crucial for aggregation and toxicity of three other amyloidogenic proteins, namely amyloid β peptide (Aβ), prion protein (PrP) and islet amyloid polypeptide (IAPP), leading us to believe that this might be the part of the molecule responsible for causing aggregation. Secondary structure prediction analysis of NAC indicated that the N‐terminal half was likely to form a β‐structure whereas the C‐terminal half was likely to form an α‐helix. NAC in solution altered from random coil to β‐sheet structure upon ageing, a process that has previously been shown to lead to fibril formation. To delineate the region of NAC responsible for aggregation we synthesised two fragments, NAC‐(1−18)‐peptide and NAC‐(19−35)‐peptide, and examined their physicochemical properties. Upon incubation, solutions of NAC‐(1−18)‐peptide became congophilic and aggregated to form fibrils of diameter 5−10 nm, whereas NAC‐(19−35)‐peptide did not bind Congo Red and remained in solution. Circular dichroism spectroscopy was used to study the secondary structure of NAC and the two fragments. In trifluoroethanol/water mixtures, NAC and NAC‐(19−35)‐peptide adopted α‐helical structure but NAC‐(1−18)‐peptide did not. NAC‐(1−18)‐peptide and NAC formed β‐sheet in acetonitrile/water mixtures more readily than did NAC‐(19−35)‐peptide. CD spectra of NAC or NAC‐(1−18)‐peptide in aqueous solution indicate the formation of β‐sheet on ageing. We propose that the N‐terminal region of NAC is the principal determinant of aggregation. Our results indicate that NAC resembles Aβ, and other amyloidogenic proteins, in that aggregation is dependent upon β‐sheet development. These results lend support to a role for NAC in the development of neurodegenerative disease.