A non-toxic hydrazone with potential anti-Alzheimer activity: this organic ligand disrupts anomalous metal–Aβ(1–40) interactions, and, thus, seems suitable as a metal-protein attenuating compound.

Although normal aging presents an accumulation of copper and iron in the brain, this becomes more relevant in neurodegeneration. α-Synuclein (α-Syn) misfolding has long been linked with the development of Parkinson's disease (PD). Copper binding promotes aggregation of α-Syn, as well as generalized oxidative stress. In this sense, the use of therapies that target metal dyshomeostasis has been in focus in the past years. Metal–Protein Attenuating Compounds (MPACs) are moderate chelators that aim at disrupting specific, abnormal metal–protein interactions. Our research group has now established that N-acylhydrazones compose a set of truly encouraging MPACs for the bioinorganic management of metal-enhanced aggregopathies. In the present work, a novel ligand, namely 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone (X1INH), is reported. We describe solution studies on the interaction and affinity of this compound for copper(II) ions showing that a fine tuning of metal-affinity was achieved. A series of in vitro biophysical NMR experiments were performed in order to assess the X1INH ability to compete with α-Syn monomers for the binding of both copper(I) and copper(II) ions, which are central in PD pathology. A preference for copper(I) has been observed. X1INH is less toxic to human neuroglioma (H4) cells in comparison to structure-related compounds. Finally, we show that treatment with X1INH results in a higher number of smaller, less compact inclusions in a well-established model of α-Syn aggregation. Thus, X1INH constitutes a promising MPAC for the treatment of Parkinson's disease.

With the increase in life expectancy registered in the past few decades, the prevalence of various medical conditions related to aging has been observed, such as dementia and related neurodegenerative conditions. The number of patients afflicted with these conditions is expected to significantly increase in the coming years. The growing social impact of dementia underlines the need for research aimed at identifying and better understanding this type of condition. Among neurodegenerative diseases, amyloidogenic diseases, in particular Alzheimer's disease (AD), are currently the most common form of dementia. Over the years, several hypotheses have been raised regarding the etiology of AD, such as the cholinergic, glutamatergic, amyloid cascade, oligomeric, metallic and diabetes type 3 hypotheses. Unfortunately, no cure is yet available for this disease, only drugs that aid in controlling the symptoms. This review article conducts a comprehensive approach of the main etiological hypotheses of AD, as well as the treatment prospects associated with each hypothesis