Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration

There is an emerging link between the accumulation of iron in the brain and abnormal tau pathology in a number of neurodegenerative disorders, such as Alzheimer's disease (AD). Studies have demonstrated that iron can regulate tau phosphorylation by inducing the activity of multiple kinases that promote tau hyperphosphorylation and potentially also by impacting protein phosphatase 2A activity. Iron is also reported to induce the aggregation of hyperphosphorylated tau, possibly through a direct interaction via a putative iron binding motif in the tau protein, facilitating the formation of neurofibrillary tangles (NFTs). Furthermore, in human studies high levels of iron have been reported to co-localize with tau in NFT-bearing neurons. These data, together with our own work showing that tau has a role in mediating cellular iron efflux, provide evidence supporting a critical tau:iron interaction that may impact both the symptomatic presentation and the progression of disease. Importantly, this may also have relevance for therapeutic directions, and indeed, the use of iron chelators such as deferiprone and deferoxamine have been reported to alleviate the phenotypes, reduce phosphorylated tau levels and stabilize iron regulation in various animal models. As these compounds are also moving towards clinical translation, then it is imperative that we understand the intersection between iron and tau in neurodegeneration. In this article, we provide an overview of the key pathological and biochemical interactions between tau and iron. We also review the role of iron and tau in disease pathology and the potential of metal-based therapies for tauopathies.