Aluminium Binding to Modified Amyloid-β Peptides: Implications for Alzheimer’s Disease

Aluminium (Al) is clearly neurotoxic and considerable evidence exists that Al may play a role in the aetiology or pathogenesis of Alzheimer&rsquo
s disease (AD). Nevertheless, the link between AD pathology and Al is still open to debate. Therefore, we investigated here the interaction of aluminium ions with two A&beta
peptide fragments and their analogues. First, we synthesised by the Fmoc/tBu solid-phase peptide synthesis (SPPS) strategy using an automated peptide synthesiser two new peptides starting from the A&beta
(1&ndash
16) native peptide fragment. For this purpose, the three histidine residues (H6, H13, and H14) of the A&beta
16) peptide were replaced by three alanine and three serine residues to form the modified peptides A&beta
16)A36,13,14 and A&beta
16)S36,13,14 (primary structures: H-1DAEFRADSGYEVAAQK16-NH2 and H-1DAEFRSDSGYEVSSQK16-NH2). In addition, the A&beta
(9&ndash
16) peptide fragment (H-9GYEVHHQK16-NH2) and its glycine analogues, namely A&beta
16)G110, (H-9GGEVHHQK16-NH2), A&beta
16)G213,14 (H-9GYEVGGQK16-NH2), and A&beta
16)G310,13,14 (H-9GGEVGGQK16-NH2), were manually synthesised in order to study Al binding to more specific amino acid residues. Both the peptides and the corresponding complexes with aluminium were comparatively investigated by mass spectrometry (MS), circular dichroism spectroscopy (CD), atomic force microscopy (AFM), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR). Al&ndash
peptide molecular ions and Al-fragment ions were unambiguously identified in the MS and MS/MS spectra. AFM images showed dramatic changes in the film morphology of peptides upon Al binding. Our findings from the investigation of N-terminal 1-16 and even 9-16 normal and modified sequences of A&beta
peptides suggest that they have the capability to be involved in aluminium ion binding associated with AD.