THE INFLUENCE OF THE CENTRAL REGION CONTAINING RESIDUES-19-25 ON THE AGGREGATION PROPERTIES AND SECONDARY STRUCTURE OF ALZHEIMERS BETA-AMYLOID PEPTIDE

Alzheimer's beta-amyloid peptide (A beta) is a 39- to 43-amino-acid pe ptide that is the major component of neuritic plaques found in Alzheim er's disease (AD). The central region of A beta plays a crucial role i n many of its properties, including aggregation, neurotoxicity, proteo lytic processing and interactions with other proteins, such as apolipo protein E. Two mutations in this region, Ala21-->Gly and Glu22-->Gln, give rise to early onset forms of disease. We have studied several pep tides based on the central region of A beta in order to clarify the in fluence of specific amino acid residues on physicochemical behaviour. To avoid difficulties due to oxidation of Met35, the latter was replac ed by the amino acid isostere, norleucine (Ahx), giving [Ahx35]A beta- (25-35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of A beta, forming the corresponding 23-, 21- and 19-35 derivatives, resulted in peptides th at aggregated to form fibrils of diameter 6-10 nm. The rate of aggrega tion was more rapid as peptide length increased. Circular dichroism sp ectra of aged solutions of peptides revealed that aggregation was acco mpanied by a transition from random structure to beta sheet for some, but not all, peptides. The mutation from Ala to Gly at position 21 inc reased the rate of aggregation and altered the tendency to adopt secon dary structure in the direction away from a helix and towards beta she et. 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 homolog ues.