The English (H6R) Mutation of the Alzheimer’s Disease Amyloid-β Peptide Modulates Its Zinc-Induced Aggregation

Abstract

The coordination of zinc ions by histidine residues of amyloid-beta peptide (Aβ) plays a critical role in the zinc-induced Aβ aggregation implicated in Alzheimer’s disease (AD) pathogenesis. The histidine to arginine substitution at position 6 of the Aβ sequence (H6R, English mutation) leads to an early onset of AD. Herein, we studied the effects of zinc ions on the aggregation of the Aβ42 peptide and its isoform carrying the H6R mutation (H6R-Aβ42) by circular dichroism spectroscopy, dynamic light scattering, turbidimetric and sedimentation methods, and bis-ANS and thioflavin T fluorescence assays. Zinc ions triggered the occurrence of amorphous aggregates for both Aβ42 and H6R-Aβ42 peptides but with distinct optical properties. The structural difference of the formed Aβ42 and H6R-Aβ42 zinc-induced amorphous aggregates was also supported by the results of the bis-ANS assay. Moreover, while the Aβ42 peptide demonstrated an increase in the random coil and β-sheet content upon complexing with zinc ions, the H6R-Aβ42 peptide showed no appreciable structural changes under the same conditions. These observations were ascribed to the impact of H6R mutation on a mode of zinc/peptide binding. The presented findings further advance the understanding of the pathological role of the H6R mutation and the role of H6 residue in the zinc-induced Aβ aggregation.

Chapter 7. Role of Metal Ions in Alzheimer's Disease: Mechanistic Aspects Contributing to Neurotoxicity

“…Mainly, EOAD variants as well as NT forms have been studied. As a general trend and in line with the amyloid cascade hypothesis, the EOAD variants show higher propensity to self-assemble in presence of Cu(II) 29 or Zn(II) 28 with respect to the Aβ1-x counterparts. For Aβ4-40 isoform, Cu(II) has a similar effect than on the Aβ1-40.…”

“…25 In addition, in familial mutants developing EOAD, amino-acid residues able to bind metal ions (histidine (His), aspartate (Asp) are mutated while the self-assembly propensity of the peptides is modified. [27][28][29]…”

Disulfide Dimerization of Neuronal Calcium Sensor-1: Implications for Zinc and Redox Signaling

“…These proteins include the following: SOD and TDP-43 in ALS; amyloid-beta, tau, and p75 neurotrophin receptors in Alzheimer's disease; synuclein in Parkinson's disease; HTT in Huntington's disease; androgen receptors in spinal and bulbar muscular atrophy; prion in prion-related diseases; ataxins in spinocerebellar ataxias [88,89], myocilin in glaucoma [90], and apparently recoverin and arrestin in AMD [33,91]. Interestingly, many proteinopathies are associated with aberrantly increased levels of free zinc, whereas respective disulfide-forming proteins commonly bind this metal, thereby mediating its neurotoxic effects [40,42,45,[92][93][94]. The joint action of two factors, namely excessive Zn 2+ binding and disulfide bonding, increases the susceptibility of certain neuronal proteins to misfolding and aggregation, the wellestablished hallmarks of neurodegeneration.…”

Role of the English (H6R) Mutation on the Structural Properties of Aβ40 and Aβ42 Owing to the Histidine Tautomeric Effect

“…12 Compared with a zinc-induced Aβ42 aggregation as the result of increased random coil and β-sheet content, a zinc-induced Aβ42 H6R aggregation showed no appreciable structural changes under the same conditions. 15 In addition, an H6R mutation also changed the net charge of Aβ and increased the hydrophobicity. 16,17 Different starting aggregation states of the protein and experimental conditions can produce different structural features, 18 which are sensitive to control polymorphic fibrils.…”

“…It was discovered that Aβ40 H6R does not accelerate the nucleation phase but selectively promotes the elongation phase of amyloid fibril formation . Compared with a zinc-induced Aβ42 aggregation as the result of increased random coil and β-sheet content, a zinc-induced Aβ42 H6R aggregation showed no appreciable structural changes under the same conditions . In addition, an H6R mutation also changed the net charge of Aβ and increased the hydrophobicity. , …”