Alzheimer's β-amyloid peptide (Aβ) is a 39- to 43-amino-acid peptide that is the major component of neuritic plaques found in Alzheimer's disease (AD). The central region of Aβ plays a crucial role in many of its properties, including aggregation, neurotoxicity, proteolytic processing and interactions with other proteins, such as apolipoprotein E. Two mutations in this region, Ala21→Gly and Glu22→Gln, give rise to early onset forms of disease. We have studied several peptides based on the central region of Aβ in order to clarify the influence of specific amino acid residues on physicochemical behaviour. To avoid difficulties due to oxidation of Met35, the latter was replaced by the amino acid isostere, norleucine (Ahx), giving [Ahx35]Aβ-(25-35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of Aβ, forming the corresponding 23-, 21- and 19-35 derivatives, resulted in peptides that aggregated to form fibrils of diameter 6-10 nm. The rate of aggregation was more rapid as peptide length increased. Circular dichroism spectra of aged solutions of peptides revealed that aggregation was accompanied by a transition from random structure to β sheet for some, but not all, peptides. The mutation from Ala to Gly at position 21 increased the rate of aggregation and altered the tendency to adopt secondary structure in the direction away from α helix and towards β sheet. In individuals with the Ala21→Gly mutation, these results would suggest that truncated species with N-termini in the region containing residues 17-20 would be more amyloidogenic than the wild type homologues.
|Number of pages||10|
|Journal||European Journal of Biochemistry|
|Publication status||Published - Sept 15 1998|
- Alzheimer's disease
- Aβ aggregation
- Secondary structure
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