Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Aβ42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease

Abstract

Metals are found associated with β-pleated sheets of Aβ42 in vivo and may be involved in their formation. Metal chelation has been proposed as a therapy for Alzheimer's disease on the basis that it may safely dissolve precipitated Aβ peptides. We have followed fibrillisation of Aβ42 in the presence of an additional metal ion (Al(III), Fe(III), Zn(II), Cu(II)) over a period of 32 weeks and we have investigated the dissolution of these aged peptide aggregates in the presence of both desferrioxamine (DFO) and ethylenediaminetetraacetic acid (EDTA). Aβ42 either alone or in the presence of Al(III) or Fe(III) formed β-pleated sheets of plaque-like amyloids which were dissolved upon incubation with either chelator. Zn(II) inhibited whilst Cu(II) prevented the formation of β-pleated sheets of Aβ42 and neither of these influences were affected by incubation of the aged peptide aggregates with either DFO or EDTA. Freshly prepared solutions of Aβ42 either alone or in the presence of added Al(III) or Fe(III) did not form β-pleated amyloid in the presence of DFO when incubated for up to 8 weeks. EDTA did not prevent β-pleated amyloid formation in the same treatments and promoted β-pleated amyloid formation in the presence of either Zn(II) or Cu(II). The presence of significant concentrations of Al(III) and Fe(III) as contaminants of 'Aβ42 only' preparations suggested that both of these metals were involved in either triggering the formation or stabilising the structure of β-pleated amyloid. If the formation of such amyloid is critical to the aetiology of AD then the chelation of Al(III) and Fe(III) may prove to be a protective mechanism whilst the chelation of Cu(II) and Zn(II) without also chelating Al(III) and Fe(III) might actually exacerbate the condition.

Thermal aggregation of β-lactoglobulin in presence of metal ions

“…Then, as a function of parameters like solvent's pH and metal concentration, these two ions have shown different behaviors; in particular, under physiological conditions, the amyloid peptide has a higher propensity to bind zinc, whereas, under mildly acidic conditions, as in physiological acidosis following an inflammatory process, copper is preferentially bound; in other words, zinc can protect against copper toxicity, which is induced by acidosis [12,13]. In addition, studies with different concentrations of copper and zinc have shown that these metals prevent fibril formation of amyloid peptide by promoting the formation of no fibril aggregates [8,[14][15][16], like oligomeric aggregates that are more neurotoxic than the same fibrils [17][18][19][20][21][22][23][24]. Finally, other results obtained by structural studies, have shown that this peptide has two metal binding sites with higher and lower affinity: copper in high affinity site is coordinated in a planar configuration with three histidines and terminus or Tyr10 and this binding site is able to bind also a zinc ion [21,22,25].…”

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

“…Transition metal ion chelators-One hypothesis that remains viable is that transition metal ions, including Al (III), Fe (III), Zn (II), and Cu (II), cause neurotoxicity and neurodegeneration (241)(242)(243), including in the earliest stages of AD (244). Excess accumulation of transition metal ions promotes oxidative stress, apoptosis, and aggregation and fibrillarization of hyper-phosphorylated tau (245) and AβPP-Aβ42 (243,246). Oxidative stress is mediated by the formation of hydroxyl radicals following interactions between iron and hydrogen peroxide.…”

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

“…67 Indeed, the prototype iron chelator, deferrioxamine (DFO), prevented the formation of ␤-pleated sheets of A␤ and dissolved preformed ␤-pleated sheets of plaque-like amyloid. 68 Also, ironinduced aggregation of hyperphosphorylated (tau), the major constituent of neurofibrillary tangles. 69 A direct link between iron metabolism and AD pathogenesis was provided recently by Rogers et al 70 who described the presence of an IRE in the 5' untranslated region (5'UTR) of the APP transcript.…”