Mercury (Hg) exposure is a possible risk factor for Alzheimer's disease (AD). Some studies reported higher Hg levels in AD patients, but evidence is inconclusive. Mechanisms linking Hg exposure to AD neuropathology remain to be found. The hallmark of AD brains is deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides. Here, we use transmission electron microscopy and biophysical spectroscopy techniques to study in vitro interactions between inorganic Hg and pathologically relevant Aβ(1–40) and Aβ(4–40) variants and the Aβ(1–40)(H6A, H13A, H14A) mutant. For the first time, effects on Aβ aggregation of both Hg(I) and Hg(II) are compared. Hg(II) binds Aβ(1–40) with apparent binding affinity of 28 ± 8 μM, at 20 °C in 20 mM MES buffer, pH 7.3. The N-terminal His6, His13, and His14 residues are involved in binding coordination. Hg(II) binding induces structural alterations (coil–coil interactions) in Aβ monomers positioned in membrane-mimicking SDS micelles. Equimolar amounts of either Hg(I) or Hg(II) inhibit normal Aβ fibrillation by directing aggregation towards forming large amorphous aggregates. All these structural rearrangements may be relevant for the harmful Aβ aggregation processes involved in AD brain pathology. Inducing protein misfolding and aggregation might be a general toxic mechanism of mercury.

Because silver is toxic to microbes, but not considered toxic to humans, the metal has been used as an antimicrobial agent since ancient times. Today, silver nanoparticles and colloidal silver are used for antibacterial purposes, and silver-peptide and similar complexes are being developed as therapeutic agents. Yet, the health effects of silver exposure are not fully understood, nor are the molecular details of silver-protein interactions. In Alzheimer’s disease, the most common form of dementia worldwide, amyloid-β (Aβ) peptides aggregate to form soluble oligomers that are neurotoxic. Here, we report that monovalent silver ions (Ag⁺) bind wildtype Aβ₄₀ peptides with a binding affinity of 25 ± 12 µM in MES buffer at 20 °C. Similar binding affinities are observed for wt Aβ₄₀ peptides bound to SDS micelles, for an Aβ₄₀(H6A) mutant, and for a truncated Aβ(4–40) variant containing an ATCUN (Amino Terminal Cu and Ni) motif. Weaker Ag⁺ binding is observed for the wt Aβ₄₀ peptide at acidic pH, and for an Aβ₄₀ mutant without histidines. These results are compatible with Ag⁺ ions binding to the N-terminal segment of Aβ peptides with linear bis-his coordination. Because the Ag⁺ ions do not induce any changes in the size or structure of Aβ₄₂ oligomers, we suggest that Ag⁺ ions have a minor influence on Aβ toxicity.

Human calcitonin is a 32-residue peptide hormone that binds to the calcitonin receptor (CTR) and is involved in calcium regulation. The amino acid sequence displays a hydrophilic central segment flanked by hydrophobic C- and N-terminal regions with a net charge of zero at neutral pH. This makes the molecule amphiphilic and conformationally flexible, and different CTR variants preferentially recognize different structural conformations of calcitonin. The peptide is secreted from the thyroid gland and is overproduced in some forms of thyroid cancer and can then form cell-toxic aggregates. Characterizing the structural properties of calcitonin under different conditions is, therefore, important for understanding its receptor-binding and self-aggregation properties. Here, we used circular dichroism (CD) spectroscopy to monitor the secondary structure of human calcitonin in different environments. Calcitonin monomers were found to display a random coil structure with a significant amount of PPII-helix components in phosphate buffer, pH 7.3, at physiological temperatures. When agitated, the peptide formed soluble aggregates over time with mainly an antiparallel β-sheet secondary structure. In the presence of micelles of differently charged surfactants, monomeric calcitonin formed a pure α-helix structure with cationic CTAB, a combination of α-helix and β-sheet with anionic SDS and with zwitterionic SB3-14, and remained mainly random coil with noncharged DDM. Thus, the charge of the surfactant headgroup was found to be an important parameter for calcitonin’s interactions with membrane-mimicking micelles. Similar but not identical interactions with the surfactants were observed under the oxidizing and reducing conditions.

Background: Leaded fuel was banned in South Africa in 2006, in order to improve human health and reduce environmental pollution. Lead (Pb) has been suggested to contribute to the development of neurodegenerative disorders, and the role of respiratory exposure to Pb from petrol fumes should not be neglected in this context. In addition to Pb, petrol contains various harmful chemicals including other neurotoxic metals and hydrocarbons.

Objectives and Methods: Here, we investigated concentrations of Pb and other metals in blood from petrol station forecourt attendants (n = 38), taxi drivers (n = 21), and unexposed controls (n = 36). Taxi drivers and forecourt attendants were divided into three groups each, based on number of years worked. A questionnaire was designed to investigate the health status of the participants. Blood samples were collected by medical professionals and analyzed for metal concentrations by ICP-MS.

Results: A positive correlation between number of years worked and Pb blood concentrations was found. The highest Pb concentration (60.2 µg/L) was observed in a forecourt attendant who had worked 11–20 years, and the average Pb concentration in this group (24.5 µg/L) was significantly (p < 0.05) higher than in forecourt attendants who had worked 2–5 years (10.4 µg/L). Some individuals had elevated concentrations of manganese, arsenic, cadmium, chromium and cobalt, yet not significantly elevated at the group level. The blood levels of arsenic appeared to be related to smoking. Mood swings, dizziness, headaches and tiredness were reported by the workers.

Conclusion: Blood Pb concentrations in petrol station forecourt attendants and taxi drivers exposed to leaded petrol are elevated and correlate to exposure time. A health monitoring program should be erected for all individuals working in these industries, and preventive measures should be implemented to eliminate metal exposure from petrol.

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal–protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.

Metal wire is in modern society manufactured by drawing metal rods through dies with conical holes of decreasing diameters, until the desired thickness is obtained. The history and origin of this technique remains unclear, although it was likely developed from earlier wire-making techniques such as strip-drawing and roll-drawing. Proper wire-drawing was an established technology in Europe during the High Middle Ages, and numerous draw-plates have been found at Scandinavian Viking Age trading centers. Here, we report the technical examination of an iron draw-plate found in Uppsala in central Sweden. The draw-plate was excavated in a Vendel Period fine metals workshop, located immediately next to the royal hall in Old Uppsala, the central building of the royal estate in the 6th −8th c. X-ray and scanning electron microscopy (SEM) analysis of the draw-plate revealed silver particles in the plate’s holes, indicating drawing of silver wire. The plate is dated to the 6th – 8th c., which makes it one of the oldest confirmed tools for wire-drawing so far encountered. The presence of this tool in the workshop indicates that some high-quality jewelry in this region was locally produced. Thus, the finding of this draw-plate increases our understanding of Vendel Period jewelry production, and of the social organization of this craft.

The interaction between human Growth Hormone (hGH) and hGH Receptor (hGHR) has basic relevance to cancer and growth disorders, and hGH is the scaffold for Pegvisomant, an anti-acromegaly therapeutic. For the latter reason, hGH has been extensively engineered by early workers to improve binding and other properties. We are particularly interested in E174 which belongs to the hGH zinc-binding triad; the substitution E174A is known to significantly increase binding, but to now no explanation has been offered. We generated this and several computationally-selected single-residue substitutions at the hGHR-binding site of hGH. We find that, while many successfully slow down dissociation of the hGH-hGHR complex once bound, they also slow down the association of hGH to hGHR. The E174A substitution induces a change in the Circular Dichroism spectrum that suggests the appearance of coiled-coiling. Here we show that E174A increases affinity of hGH against hGHR because the off-rate is slowed down more than the on-rate. For E174Y (and certain mutations at other sites) the slowdown in on-rate was greater than that of the off-rate, leading to decreased affinity. The results point to a link between structure, zinc binding, and hGHR-binding affinity in hGH.

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 Alzheimer’s disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the 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. The 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. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation. 

Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different chemical and physical properties, their complexation with the cargo and characteristics of the resulting nanoparticles largely depends on the properties of the surrounding environment, i.e., solution. Here, we show that the solvent used for the initial dissolving of a CPP determines the properties of the resulting CPP particles formed in an aqueous solution, including the activity and toxicity of the CPP–NA complexes. Using different biophysical methods such as dynamic light scattering (DLS), atomic force microscopy (AFM), transmission and scanning electron microscopy (TEM and SEM), we show that PepFect14 (PF14), a cationic amphipathic CPP, forms spherical particles of uniform size when dissolved in organic solvents, such as ethanol and DMSO. Water-dissolved PF14, however, tends to form micelles and non-uniform aggregates. When dissolved in organic solvents, PF14 retains its α-helical conformation and biological activity in cell culture conditions without any increase in cytotoxicity. Altogether, our results indicate that by using a solvent that matches the chemical nature of the CPP, the properties of the peptide–cargo particles can be tuned in the desired way. This can be of critical importance for in vivo applications, where CPP particles that are too large, non-uniform, or prone to aggregation may induce severe consequences.

Copper is an indispensable biometal, primarily serving as a redox-competent cofactor in numerous proteins. Apart from preformed copper-binding sites within the protein structures, small peptide motifs exist called ATCUN, which are composed of an N-terminal tripeptide XZH, able to bind Cu(II) ions in exchangeable form. These motifs are common for serum albumin, but they are also present in a wide range of proteins and peptides. These proteins and peptides can be involved in copper metabolism, and copper ions can affect their biological role. The distribution of copper between the ATCUN peptides, including truncated amyloid-β (Aβ) peptides Aβ4–42 and Aβ11–42, which may be involved in Alzheimer’s disease pathogenesis, is mainly determined by their concentrations and relative Cu(II)-binding affinities. The Cu(II)-binding affinity (log K_d) of several ATCUN peptides, determined by different methods and authors, varies by more than three orders of magnitude. This variation may be attributed to the chemical properties of peptides but can also be influenced by the differences in methods and experimental conditions used for the determination of K_d. In the current study, we performed direct competition experiments between selected ATCUN peptides and HSA by using an LC-ICP MS-based approach. We demonstrated that ATCUN and truncated Aβ peptides Aβ4–16 and Aβ11–15 bind Cu(II) ions with an affinity similar to that for HSA. Our results demonstrate that ATCUN motifs cannot compete with excess HSA for the binding of Cu(II) ions in the blood and cerebrospinal fluid.