The influence of the central region containing residues 19-25 on the aggregation properties and secondary structure of Alzheimer's beta-amyloid peptide.
Alzheimer's beta-amyloid peptide (Abeta) 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 Abeta 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 Abeta 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]Abeta-(25-35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of Abeta, 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 beta 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 alpha helix and towards beta 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.
Peptide and Protein Engineering Centre, School of Biology & Biochemistry, The Queen's University of Belfast, UK.
O M
OM
El-Agnaf
D J
DJ
Guthrie
D M
DM
Walsh
G B
GB
Irvine
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D005612:Freeze Drying; D006801:Humans; D008854:Microscopy, Electron; D010449:Peptide Mapping; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012995:Solubility
D016229:Amyloid beta-Peptides