Multivariate effects of pH, salt, and Zn2+ ions on Aβ40 fibrillation

Abstract

Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimer’s disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregation of the Aβ peptides. Here, we investigate the multivariate effects of varied pH, ionic strength and Zn2+ on Aβ40 fibrillation kinetics. Our results reveal that Aβ fibrillation kinetics are strongly affected by pH and ionic strength suggesting the importance of electrostatic interactions in regulating Aβ40 fibrillation. More interestingly, the presence of Zn2+ ions can further alter or even reserve the role of pH and ionic strength on the amyloid fibril kinetics, suggesting the importance of amino acids like Histidine that can interact with Zn2+ ions. Both pH and ionic strength regulate the secondary nucleation processes, however regardless of pH and Zn2+ ions, ionic strength can also modulate the morphology of Aβ40 aggregates. These multivariate effects in bulk solution provide insights into the correlation of pH-, ionic strength- or Zn2+ ions changes with amyloid deposits in AD brain and will deepen our understanding of the molecular pathology in the local brain microenvironment.

Protein Oligomer Engineering: A New Frontier for Studying Protein Structure, Function, and Toxicity

“…Endogenously driven [1,[52][53][54][55][56] Implementation for in vivo and in vitro systems Structurally unstable, stoichiometrically undefined Detergent micelles [24, 26,, 57, 58] Small size ideal for solution NMR and MS measurements Structurally unstable, stoichiometrically undefined Chemical scaffolds [59][60][61][62][63][64] Defined oligomer stoichiometry and structure after chemical modification…”

“…[54] Aβ oligomer stability and formation rate can be affected by factors such as temperature, ionic strength, and pH. [55,56] For example, higher temperatures and acidic pH can promote the formation of Aβ oligomers, while lower temperatures and neutral pH can inhibit their formation. [56] This sensitivity to solution conditions makes it challenging to characterize the toxic forms of Aβ oligomers, as they can be unstable and heterogeneous.…”

Biophysical and Integrative Characterization of Protein Intrinsic Disorder as a Prime Target for Drug Discovery

“…This term can also be temperature-dependent on accounting for the upper and lower critical solution temperatures [ 202 ] and salt-dependent to account for the salting-out effect at high salt concentrations [ 203 ]. Additional angle and dihedral terms can be introduced to capture the residue-specific secondary structure propensities of the chain [ 204 , 205 ]. The entire framework is flexible and easy to re-optimize with growing experimental measurements [ 190 , 199 , 200 , 201 ] and can be extended to biomolecules such as nucleic acids [ 206 ].…”

Manganese Ion-Induced Amyloid Fibrillation Kinetics of Hen Egg White-Lysozyme in Thermal and Acidic Conditions

“…Besides, the specific roles of transition metal ions in protein denaturation are well-known as “Hofmeister series” according to the sequence of their action strength. 19 , 20 It is worth noting that the disparate effects of Zn 2+ , 21 , 22 Cu 2+ , 23 , 24 Al 3+ , 25 and Mn 2+ 26 , 27 on denaturation of various proteins were reported. For example, a double-edged effect of Al 3+ ions on the HEWL amyloid fibrillation kinetics has been revealed recently 25 that Al 3+ ions accelerate the conformational transformations from α-helices to organized β-sheets, in addition to postponing α-helix degradation.…”

“…Because HEWL in the nature state is resistant to denaturation, previous studies on the denaturation of HEWL were mainly carried out in unnatural conditions, like acidic and thermal treatment. , Moreover, the promotion or inhibition effects of ethanol, guanidine hydrochloride, alkaline pH, sunset yellow, and succinimide, even including silver nanoparticles, were also discussed on amyloid fibrils formation. Besides, the specific roles of transition metal ions in protein denaturation are well-known as “Hofmeister series” according to the sequence of their action strength. , It is worth noting that the disparate effects of Zn 2+ , , Cu 2+ , , Al 3+ , and Mn 2+ , on denaturation of various proteins were reported. For example, a double-edged effect of Al 3+ ions on the HEWL amyloid fibrillation kinetics has been revealed recently that Al 3+ ions accelerate the conformational transformations from α-helices to organized β-sheets, in addition to postponing α-helix degradation.…”