Characterising the spatial and temporal brain metal profile in a mouse model of tauopathy

Rao, Shalini S; Lago, Larissa; Vega, Raquel González de; Bray, Lisa; Hare, Dominic J.; Clases, David; Doble, Philip; Adlard, Paul A.

doi:10.1039/c9mt00267g

Cited by 26 publications

(19 citation statements)

References 109 publications

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“…Drug treatments were performed in a mixed-gender cohort and commenced at 12 months of age. Our previous studies demonstrated that rTg4510 mice have profound behavioral deficits at this age, in addition with a significant accumulation of brain iron [37] and tau pathology, therefore allowing us to examine the use of DFP as a treatment strategy. Mice were housed in Techniplast IVC cages with free access to mouse chow and water.…”

Section: Animalsmentioning

confidence: 99%

Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology

et al. 2021

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The accumulation of neurofibrillary tangles (NFTs), which is composed of abnormally hyperphosphorylated tau aggregates, is the classic neuropathology associated with cognitive dysfunction in tauopathies such as Alzheimer's disease (AD). However, there is an emerging theory suggesting that dysregulation in cerebral iron may contribute to NFT formation. Iron is speculated to bind to tau and induce conformational changes of the protein, potentially leading to subsequent aggregation and cognitive decline. Deferiprone (DFP) is a clinically available iron chelator, which has demonstrated potential therapeutic advantages of chelating iron in neurodegenerative disorders, and is currently in clinical trials for AD. However, its effect on tau pathology remains unclear. Here, we report the effects of short-term DFP treatment (4 weeks, 100 mg/kg/daily, via oral gavage) in a mixedgender cohort of the rTg (tauP301L) 4510 mouse model of tauopathy. Our results revealed that DFP improved Y-maze and open field performance, accompanied by a 28% decrease in brain iron levels, measured by inductively coupled plasma mass spectrometry (ICP-MS) and reduced AT8-labeled p-tau within the hippocampus in transgenic tau mice. This data supports the notion that iron may play a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders that can be modulated by the clinically available metal chelator DFP.

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Section: Animalsmentioning

confidence: 99%

Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology

et al. 2021

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“…Drug treatment commenced at 4 months and concluded at the end of 7 months of age. This age was chosen to begin treatment as our previous work demonstrated a significant age-related increase in brain iron levels from 4 months to 7 months of age in rTg4510 compared to age-matched WT mice [46]. Mice were housed in Techniplast IVC cages with free access to mouse chow and water.…”

Section: Animalsmentioning

confidence: 99%

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

Rao

Portbury

Lago

et al. 2020

JAD

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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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“…The oxidation process slows down or excludes the regular action of the Aβ and tau protein [148]. 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].…”

Section: Ferroptosis In Alzheimer's Diseasementioning

confidence: 99%

Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

Reichert

Freitas

Sampaio-Silva

et al. 2020

IJMS

252

148

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Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer’s, Parkinson’s, and Huntington’s diseases, has also been addressed.

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Characterising the spatial and temporal brain metal profile in a mouse model of tauopathy

Abstract: 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).

Cited by 26 publications

References 109 publications

Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology

Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology

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

Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

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