Aluminium (Al) is clearly neurotoxic and considerable evidence exists that Al may play a role in the aetiology or pathogenesis of Alzheimer’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 Aβ 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 Aβ_(1–16) native peptide fragment. For this purpose, the three histidine residues (H⁶, H¹³, and H¹⁴) of the Aβ_(1–16) peptide were replaced by three alanine and three serine residues to form the modified peptides Aβ_(1–16)A₃^6,13,14 and Aβ_(1–16)S₃^6,13,14 (primary structures: H-¹DAEFRADSGYEVAAQK¹⁶-NH₂ and H-¹DAEFRSDSGYEVSSQK¹⁶-NH₂). In addition, the Aβ_(9–16) peptide fragment (H-⁹GYEVHHQK¹⁶-NH₂) and its glycine analogues, namely Aβ_(9–16)G₁¹⁰, (H-⁹GGEVHHQK¹⁶-NH₂), Aβ_(9–16)G₂^13,14 (H-⁹GYEVGGQK¹⁶-NH₂), and Aβ_(9–16)G₃^10,13,14 (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–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 Aβ peptides suggest that they have the capability to be involved in aluminium ion binding associated with AD.

Aggregation of amyloid-β peptides (Aβ) is a hallmark of Alzheimer’s disease (AD), which is affecting an increasing number of people. Hence, there is an urgent need to develop new pharmaceutical treatments which could be used to prevent the AD symptomatology. Activity-dependent neuroprotective protein (ADNP) was found to be deficient in AD, whereas NAP, an 8-amino-acid peptide (¹NAPVSIPQ⁸) derived from ADNP, was shown to enhance cognitive function. The higher tendency of zinc ion to induce Aβ aggregation and formation of amorphous aggregates is also well-known in the scientific literature. Although zinc binding to Aβ peptides was extensively investigated, there is a shortage of knowledge regarding the relationship between NAP peptide and zinc ions. Therefore, here, we investigated the binding of zinc ions to the native NAP peptide and its analog obtained by replacing the serine residue in the NAP sequence with tyrosine (¹NAPVYIPQ⁸) at various molar ratios and pH values by mass spectrometry (MS) and nuclear magnetic resonancespectroscopy (NMR). Matrix-assisted laser desorption/ionization time-of-flight (MALDI ToF) mass spectrometry confirmed the binding of zinc ions to NAP peptides, while the chemical shift of Asp¹, observed in ¹H-NMR spectra, provided direct evidence for the coordinating role of zinc in the N-terminal region. In addition, molecular modeling has also contributed largely to our understanding of Zn binding to NAP peptides.

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