Alzheimer’s disease is a severe disorder that affects millions of people worldwide. It is a very debilitating disease with no cure at the moment. The necessity of finding an effective treatment is very demanding, and the entire scientific community is putting in a lot of effort to address this issue. The major hallmark of Alzheimer’s disease is the presence of toxic aggregated species in the brain, impaired metal homeostasis, and high levels of oxidative stress. Rosmarinic acid is a well-known potent antioxidant molecule, the efficacy of which has been proved both in vitro and in vivo. In this study, we investigated the possible role played by rosmarinic acid as a mediator of the copper(II)-induced neurotoxicity. Several spectroscopic techniques and biological assays were applied to characterize the metal complexes and to evaluate the cytotoxicity and the mutagenicity of rosmarinic acid and its Cu(II) complex. Our data indicate that rosmarinic acid is able to interfere with the interaction between amyloid β and Cu(II) by forming an original ternary association.

The crystal structure of ZnZnuA from Escherichia coli reveals two metal binding sites. (i) The primary binding site, His143, is located close the His-rich loop (residues 116–138) and plays a significant role in Zn(II) acquisition. (ii) The secondary binding site involves His224. In this work, we focus on understanding the interactions of two metal ions, Zn(II) and Cu(II), with two regions of ZnuA, which are possible anchoring sites for Zn(II): Ac- 115 MKSI H GDDDD H D H AEKSDED HHH GDFNM H LW 145 -NH 2 (primary metal binding site) and Ac- 223 G H FTVNPEIQPGAQRL H E 240 -NH 2 (secondary metal binding site). The histidine-rich loop (residues 116–138) has a role in the capture of zinc(II), which is then further delivered into other regions of the protein. For both Zn(II) complexes, histidine residues constitute the main anchoring donors. In the longer, His-rich fragment, a tetrahedral complex with four His residues is formed, while in the second ligand, two imidazole nitrogens are involved in zinc(II) binding. In both cases, so-called loop structures are formed. One consists of a 125 H x H x E xxx E x H x H 137 motif with seven amino acid residues in the loop between the two central histidines, while the other is formed by a 224 H FTVNPEIQPGAQRL H 239 motif with 14 amino acid residues in the loop between the two nearest coordinating histidines. The number of available imidazoles also strongly affects the structure of copper(II) complexes; the more histidines in the studied region, the higher the pH in which amide nitrogens will participate in Cu(II) binding.

: Polyphenols are a class of compounds produced by plants, which share the ability to act as potent antioxidants. First investigations on polyphenols’ antioxidant activity are dated almost twenty years ago when their relationship and implication with the prevention and treatment of cancer was proposed for the first time. Later, in the early 2000s, the neuroprotective effects of several polyphenols were demonstrated. Nowadays, the benefits of a plethora of polyphenols have been studied, and their ameliorating effects in several disease conditions, like cancer, cardiac and neuronal diseases, are widely recognized. More than 1000 papers dealing with polyphenols and Alzheimer’s disease have been published so far, describing the antioxidant properties, the chelating metal features, and the anti-aggregating behavior of these compounds. This review aims to rationalize, from a chemical point of view, the metal complexation mechanisms of polyphenols related to two significant events of Alzheimer’s disease: oxidative stress and metal ion dyshomeostasis. To address this issue, we have herein discussed several aspects implicated in Alzheimer’s disease and polyphenols involved in treating the disease.

α-Synuclein (αSyn) constitutes the main protein component of Lewy bodies, which are the pathologic hallmark in Parkinson’s disease. αSyn is unstructured in solution but the interaction of αSyn with lipid membrane modulates its conformation by inducing an α-helical structure of the N-terminal region. In addition, the interaction with metal ions can trigger αSyn conformation upon binding and/or through the metal-promoted generation of reactive oxygen species which lead to a cascade of structural alterations. For these reasons, the ternary interaction between αSyn, copper, and membranes needs to be elucidated in detail. Here, we investigated the structural properties of copper-αSyn binding through NMR, EPR, and XAS analyses, with particular emphasis on copper(I) coordination since the reduced state is particularly relevant for oxygen activation chemistry. The analysis was performed in different membrane model systems, such as micellar sodium dodecyl sulfate (SDS) and unilamellar vesicles, comparing the binding of full-length αSyn and N-terminal peptide fragments. The presence of membrane-like environments induced the formation of a copper:αSyn = 1:2 complex where Cu+ was bound to the Met1 and Met5 residues of two helical peptide chains. In this coordination, Cu+ is stabilized and is unreactive in the presence of O2 in catechol substrate oxidation.

Galantamine is a natural alkaloid extracted from the Amaryllidaceae plants and is used as the active ingredient of a drug approved for the treatment of the early stages of Alzheimer’s disease. It mainly acts as an acetylcholinesterase (AChE) inhibitor, increasing concentrations of the acetylcholine neurotransmitter. Recent cellular studies have also shown the ability of galantamine to protect SH-SY5Y cell lines against amyloid-β (Aβ)-induced toxicity. Such investigations have supported and validated further in-depth studies for understanding the chemical and molecular features associated with galantamine-protective abilities. In addition to galantamine, other natural alkaloids are known to possess AChE inhibitory activity; among them lycorine has been extensively investigated for its antibacterial, anti-inflammatory and antitumoral activities as well. Despite its interesting biological properties, lycorine’s neuroprotective functions against Aβ-induced damages have not been explored so far. In this research study, the ability of galantamine and lycorine to suppress Aβ-induced in vitro neuronal toxicity was evaluated by investigating the chemical interactions of the two alkaloids with Aβ peptide. A multi-technique spectroscopic analysis and cellular cytotoxicity assays were applied to obtain new insights on these molecular associations. The comparison between the behaviors exhibited by the two alkaloids indicates that both compounds possess analogue abilities to interact with the amyloidogenic peptide and protect cells.