Irreversible Macromolecular Complexes

Al(III) is a rather sluggish metal ion, but its practically irreversible binding in biological systems is nevertheless rather rare. It may occur, however, in molecular aggregates, when the exchange reactions of Al(III) are slowed down because of the formation of hydrolyzed oxo- or hydroxo-bridged Al clusters wrapped around by organic compounds. Al(III) accumulated in the brain in NTFs and senile plaques (SPs) may represent such complexes. The quantitative information available on these interactions is rather limited.

Al(III) coordination has also been detected for larger oligopeptides, such as soluble amyloids Ap(1-40) and Ap(6-25) [48,49]. Recent experiments point to the basic contribution of Ap aggregation to the etiology of AD [50,51]. Besides Al(III), several transition metal ions, such as Zn(II) and the redox-active Cu(II) and Fe(III), may also be involved in amyloid binding [52].

The Al(III) binding sites of phosphorylated and nonphosphorylated fragments of neurofibrillary proteins [53,54], yielding the p-pleated sheet structure, are the Glu or phosphorylated Ser. The high stability of these Al(III) complexes [48,49] may be relevant to the mechanism through which the neurotoxin Al(III) could give rise to the formation of NFTs. Interestingly, the CD- and IR-detected interaction could not be measured by multinuclear NMR, suggesting some outersphere coordination between Al(OH)3 particles and the proteins in these aggregates [33].

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