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.
A dysregulation in the homeostasis of metals such as copper, iron and zinc is speculated to be involved in the pathogenesis of tauopathies, which includes Alzheimer's disease (AD).
Background: Abnormally hyperphosphorylated tau is a defining pathological feature of tauopathies, such as Alzheimer’s disease (AD), and accumulating evidence suggests a role for iron in mediating tau pathology that may lead to cognitive decline in these conditions. The metal chelator deferiprone (DFP), which has a high affinity for iron, is currently in clinical trials for AD and Parkinson’s disease. However, the effect of DFP on tau pathology remains underexplored. Objective: We aimed to investigate the impact of chronic DFP treatment on tau pathology using a well-characterized mouse model of tauopathy (rTg(tauP301L)4510). Methods: Animals were treated daily with DFP (100 mg/kg) via oral gavage for 16 weeks. After 14 weeks, mice were tested in the Y-maze, open field, Morris water maze, and rotorod. At the end of the study, brain tissue was collected to examine metal levels (using inductively coupled plasma-mass spectrometry) and for western blot analysis of DFP on tau and iron associated pathways. Results: DFP significantly reduced anxiety-like behavior, and revealed a trend toward improved cognitive function. This was accompanied by a decrease in brain iron levels and sarkosyl-insoluble tau. Our data also showed downregulation of the tau kinases glycogen synthase kinase 3β and cyclin dependent kinase-5 in DFP treated mice and an increase in the methylation of the catalytic subunit of protein phosphatase 2A. Conclusion: These data support the hypothesis that suggests that iron plays a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders.
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