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'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/ t Bu 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 (H ⁶ , H ¹³ , and H ¹⁴ ) of the Aβ _{( 1 - 16)} peptide were replaced by three alanine and three serine residues to form the modified peptides Aβ _(1-16) A ₃ ^6,13,14 and Aβ _(1-16) S ₃ ^6,13,14 (primary structures: H- ¹ DAEFR A DSGYEV AA QK ¹⁶ -NH ₂ and H- ¹ DAEFR S DSGYEV SS QK ¹⁶ -NH ₂ ). In addition, the Aβ _{(9 - 16)} peptide fragment (H- ⁹ GYEVHHQK ¹⁶ -NH ₂ ) and its glycine analogues, namely Aβ _{(9 - 16)} G ₁ ¹⁰ , (H- ⁹ G G EVHHQK ¹⁶ -NH ₂ ), Aβ _{(9 - 16)} G ₂ ^13,14 (H- ⁹ GYEV GG QK ¹⁶ -NH ₂ ), and Aβ _{(9 - 16)} G ₃ ^10,13,14 (H- ⁹ G G EV GG QK ¹⁶ -NH ₂ ), 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.
Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.