Characterization of Uranyl (UO₂²⁺) Ion Binding to Amyloid Beta (Aβ) Peptides: Effects on Aβ Structure and Aggregation

Abstract

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, UO 2 2+ , 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.

Hereditary Transthyretin Amyloidosis (hATTR) with Polyneuropathy Clusters Are Located in Ancient Mining Districts: A Possible Geochemical Origin of the Disease

“…It should be noted that coal mining is associated with the release of metals with genotoxic properties [ 23 ], often found in elevated concentrations in coal mine tailings and waste, and leaching into agricultural soils typically in a concentration sequence of As > Zn > Ni > Cd > Cr > Cu > Pb [ 24 ]. Coal often also contains U [ 25 ] with known neurotoxic and genotoxic properties [ 26 ].…”

Aggregation Dynamics Characteristics of Seven Different Aβ Oligomeric Isoforms-Dependence on the Interfacial Interaction

“…The occurrence of AD occurs due to the fact that proteins cannot acquire their functional folding, so aggregation into amyloid fibrils occurs . Although many factors contribute to the pathogenesis of AD, it is widely accepted that the main components of plaque accumulation are composed of abnormally folded β-amyloid (Aβ) and tau protein in brain. − Increasing evidence suggests that soluble Aβ oligomers are toxic and serve as critical targets for treating AD. , …”