Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation

Vosough

Svantesson

et al. 2023

Sci Rep

Self Cite

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aβ peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods—mainly spectroscopy and imaging techniques—to characterize Aβ/Ni(II) interactions in vitro, for different Aβ variants: Aβ(1–40), Aβ(1–40)(H6A, H13A, H14A), Aβ(4–40), and Aβ(1–42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aβ monomers. Equimolar amounts of Ni(II) ions retard Aβ aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aβ binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aβ dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aβ monomers, while in a membrane-mimicking environment (SDS micelles) coil–coil helix interactions appear to be induced. For SDS-stabilized Aβ oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aβ aggregation processes that are involved in AD brain pathology.

Section: Resultsmentioning

confidence: 74%

Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides

Vosough

Svantesson

et al. 2023

Sci Rep

Self Cite

“…In vitro, the protein aggregates contain regular fibrillar structures that can be visualised by techniques such as electron microscopy (EM) or atomic force microscopy (AFM) [49,50]. It is also possible to characterise the size and charge of the aggregates [51] as well as their aggregation rate, kinetics, formation mechanism and early oligomeric states [52,53].…”

Section: Introductionmentioning

confidence: 99%

Metals in ALS TDP-43 Pathology

Koski

Ronnevi

et al. 2021

IJMS

Self Cite

Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.

“…Uranium is a well-known neurotoxicant 34 , but the underlying molecular mechanisms and a possible role of U in neurodegenerative diseases remain unclear 44,86 . For Alzheimer's disease, several studies have investigated how Aβ peptides interact with various metal ions 28,42,129,[144][145][146][147] and with small cationic molecules 26,148 . We here interpret the current results on Aβ-uranyl interactions in the light of this earlier work.…”

Section: Discussionmentioning

confidence: 99%

Characterization of uranyl (UO₂²⁺) ion binding to amyloid beta (Aβ) peptides: effects on Aβ structure and aggregation

Vosough

Noormägi

et al. 2023

Preprint

Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions including Alzheimers disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aβ aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aβ production, and these metals bind to Aβ peptides and modulate their aggregation. Possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aβ peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aβ peptides with affinities in the micromolar range, induce structural changes in Aβ monomers and oligomers, and inhibit Aβ fibrillization. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation.