RETRACTED: The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy1

Abstract

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.

Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

“…In animal models of tauopathies, increased iron associated with aging and neurodegeneration has been observed [149]. Indeed, animals with tauopathies treated with the iron chelator deferiprone showed a trend toward improved cognitive function associated with the decrease in brain iron levels and sarkosyl-insoluble tau [150].…”

Mechanisms of Modulation of Ferroptosis and Its Role in Central Nervous System Diseases

“…Therapeutically, iron chelator desferrioxamine has already been conducted a clinical trial in AD in 1991 (Crapper McLachlan et al, 1991). A randomized, multi-center, doubleblind Phase II trial using deferiprone for AD patients (clinical trial NCT03234686) is currently ongoing in Australia (Rao et al, 2020). Moreover, as mentioned above, Se can increase the resistance of cells to ferroptosis.…”

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease

“…In addition, based on the structure of DFP with the benzothiazole moiety of ThT, compound 2d (from reference [284]) was developed, and it showed a strong Fe-chelating ability [284]. Moreover, recent animal studies showed that DFP could regulate the Aβ levels and phosphorylation of tau, leading to improved cognitive function in a transgenic mouse model of tauopathy, rTg4510 (Table 3) [285][286][287]. The results of clinical trials (phase II) of DFP are summarized in Table 1 [288].…”

“…Moreover, they could affect the aggregation of Fe(III)-Aβ 42 and disassemble preformed Fe(III)-Aβ 42 aggregates [202]. Based on multifunctionality, a few chemical agents, although they have firstly been suggested as Fe(II/III) chelators, have recently been examined for their potentials as therapeutic agents for AD in various animals (Table 3) [280][281][282][285][286][287][292][293][294].…”