Metals in alzheimer’s disease

Abstract

The brain houses high concentrations of transition metals zinc, copper and iron, which it uses for specialised neurochemistry and the synthesis of heme. It is in this high flux environment that several of the culprit proteins of Alzheimer's disease (AD) aggregate, losing function and possibly becoming toxic. These include amyloid (Ab) that aggregates outside of the cell forming plaques, and tau, which aggregates inside the neurons forming tangles. Both pathologies recruit high concentrations of metal ions. Presenilins, whose mutations cause aggressive familial AD, play a major role in metal uptake. The levels of iron in the brain rise with aging and rise even more with AD. This is caused by dissociating zinc within amyloid deposits inhibiting the iron-export activity of the Ab precursor protein (APP), which is a major component of neuronal iron efflux. We have recently found that tau plays a major role in neuronal iron homeostasis by mediating APP trafficking. The metal-centred neuropathology of AD is the target for a new class of drugs that have shown considerable promise in clinical trials. Abnormal metal homeostasis is also reflected in the periphery in AD, and may be the basis for predictive biomarkers.