Metal Ions in Alzheimer's Disease: A Key Role or Not?

Despite tremendous research efforts in universities and pharmaceutical companies, effective drugs are still lacking for the treatment of Alzheimer's disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease have not yet been clearly understood. Besides a small percentage of cases with early onset disease having a genetic origin (<5%, familial AD), most cases develop in the elderly as a sporadic form due to multiple and complex parameters of aging. Consequently, AD is spreading in all countries with a long life expectancy. AD is characterized by deposition of senile plaques made of β-amyloid proteins (Aβ) and by hyperphosphorylation of tau proteins, which have been considered as the main drug targets up to now. However, antibodies targeting amyloid aggregates, as well as enzyme inhibitors aiming to modify the amyloid precursor protein processing, have failed to improve cognition in clinical trials. Thus, to set up effective drugs, it is urgent to enlarge the panel of drug targets. Evidence of the link between AD and redox metal dysregulation has also been supported by post-mortem analyses of amyloid plaques, which revealed accumulation of copper, iron, and zinc by 5.7, 2.8, and 3.1 times, respectively, the levels observed in normal brains. Copper-amyloid complexes, in the presence of endogenous reductants, are able to catalyze the reduction of dioxygen and to produce reduced, reactive oxygen species (ROS), leading to neuron death. The possibility of using metal chelators to regenerate normal trafficking of metal ions has been considered as a promising strategy in order to reduce the redox stress lethal for neurons. However, most attempts to use metal chelators as therapeutic agents have been limited to existing molecules available from the shelves. Very few chelators have resulted from a rational design aiming to create drugs with a safety profile and able to cross the blood-brain barrier after an oral administration. In the human body, metals are handled by a sophisticated protein network to strictly control their transport and reactivity. Abnormal concentrations of certain metals may lead to pathological events due to misaccumulation and irregular reactivity. Consequently, therapeutic attempts to restore metal homeostasis should carefully take into account the coordination chemistry specificities of the concerned redox-active metal ions. This Account is focused on the role of the main biologically redox-active transition metals, iron and copper. For iron, the recent debate on the possible role of magnetite in AD pathogenesis is presented. The section devoted to copper is focused on the design of specific copper chelators as drug candidates able to regulate copper homeostasis and to reduce the oxidative damage responsible for the neuron death observed in AD brains. A short survey on non-redox-active metal ions is also included at the beginning, such as aluminum and its controversial role in AD and zinc which is a key metal ion in the brain.