The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy.

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.

[1]  P. Adlard,et al.  Characterising the spatial and temporal brain metal profile in a mouse model of tauopathy. , 2020, Metallomics : integrated biometal science.

[2]  E. Chi,et al.  Passive immunotherapies targeting amyloid beta and tau oligomers in Alzheimer's disease. , 2020, Journal of pharmaceutical sciences.

[3]  A. Bush,et al.  Targeting metals rescues the phenotype in an animal model of tauopathy. , 2018, Metallomics : integrated biometal science.

[4]  P. Adlard,et al.  Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration , 2018, Front. Mol. Neurosci..

[5]  N. Schröder,et al.  Iron chelator deferiprone rescues memory deficits, hippocampal BDNF levels and antioxidant defenses in an experimental model of memory impairment , 2018, BioMetals.

[6]  J. Uslaner,et al.  Early intervention of tau pathology prevents behavioral changes in the rTg4510 mouse model of tauopathy , 2018, PloS one.

[7]  C. Adler,et al.  Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease , 2018, Journal of neuropathology and experimental neurology.

[8]  Neena Singh,et al.  α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease , 2017, Scientific Reports.

[9]  A. Bush,et al.  Tau-mediated iron export prevents ferroptotic damage after ischemic stroke , 2017, Molecular Psychiatry.

[10]  David M. Shackleford,et al.  The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease , 2017, Acta neuropathologica communications.

[11]  L. Tönges,et al.  Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation , 2017, NeuroMolecular Medicine.

[12]  H. Kraatz,et al.  Electrochemical studies of tau protein-iron interactions—Potential implications for Alzheimer’s Disease , 2017 .

[13]  Maneesh C. Patel,et al.  Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease , 2017, Scientific Reports.

[14]  B. Roberts,et al.  Standards for Quantitative Metalloproteomic Analysis Using Size Exclusion ICP-MS , 2016, Journal of visualized experiments : JoVE.

[15]  C. Volbracht,et al.  Hyperactivity with Agitative-Like Behavior in a Mouse Tauopathy Model. , 2015, Journal of Alzheimer's disease : JAD.

[16]  J. Connor,et al.  Cp/Heph mutant mice have iron‐induced neurodegeneration diminished by deferiprone , 2015, Journal of neurochemistry.

[17]  DuhamelAlain,et al.  Targeting chelatable iron as a therapeutic modality in Parkinson's disease. , 2014 .

[18]  Chuong B. Do,et al.  Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease , 2014, Nature Genetics.

[19]  E. Teng,et al.  Loss of MAP Function Leads to Hippocampal Synapse Loss and Deficits in the Morris Water Maze with Aging , 2014, The Journal of Neuroscience.

[20]  N. Chattipakorn,et al.  Combined Therapy of Iron Chelator and Antioxidant Completely Restores Brain Dysfunction Induced by Iron Toxicity , 2014, PloS one.

[21]  G. Kontoghiorghes,et al.  Potential clinical applications of chelating drugs in diseases targeting transferrin-bound iron and other metals , 2013, Expert opinion on investigational drugs.

[22]  Tao Wang,et al.  Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease , 2013, Neurobiology of Aging.

[23]  Pu Wang,et al.  Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain , 2013, Neurochemistry International.

[24]  M. Goldenberg,et al.  Pharmaceutical approval update. , 2013, P & T : a peer-reviewed journal for formulary management.

[25]  Tao Wang,et al.  Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake , 2012, Neurochemistry International.

[26]  Michelle K. Lupton,et al.  Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases. , 2012, Human molecular genetics.

[27]  M. Youdim,et al.  The novel multi-target iron chelating-radical scavenging compound M30 possesses beneficial effects on major hallmarks of Alzheimer's disease. , 2012, Antioxidants & redox signaling.

[28]  W. Frey,et al.  Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice , 2012, Experimental Brain Research.

[29]  B. Ghetti,et al.  Frontotemporal dementia: implications for understanding Alzheimer disease. , 2012, Cold Spring Harbor perspectives in medicine.

[30]  Blaine R. Roberts,et al.  Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export , 2012, Nature Medicine.

[31]  M. Schrag,et al.  Deferiprone reduces amyloid-β and tau phosphorylation levels but not reactive oxygen species generation in hippocampus of rabbits fed a cholesterol-enriched diet. , 2012, Journal of Alzheimer's disease : JAD.

[32]  C. Janus,et al.  Sex difference in pathology and memory decline in rTg4510 mouse model of tauopathy , 2011, Neurobiology of Aging.

[33]  R. Artuch,et al.  Combined Therapy with Idebenone and Deferiprone in Patients with Friedreich’s Ataxia , 2011, The Cerebellum.

[34]  J. Götz,et al.  Animal models reveal role for tau phosphorylation in human disease. , 2010, Biochimica et biophysica acta.

[35]  Jürgen Götz,et al.  Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models , 2010, Cell.

[36]  I. Landrieu,et al.  Spectroscopic Studies of GSK3β Phosphorylation of the Neuronal Tau Protein and Its Interaction with the N-terminal Domain of Apolipoprotein E , 2010, The Journal of Biological Chemistry.

[37]  J. Trojanowski,et al.  Synergistic Interactions between Aβ, Tau, and α-Synuclein: Acceleration of Neuropathology and Cognitive Decline , 2010, The Journal of Neuroscience.

[38]  George Perry,et al.  Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. , 2010, Journal of Alzheimer's disease : JAD.

[39]  J. Kaplan,et al.  Specific iron chelators determine the route of ferritin degradation. , 2009, Blood.

[40]  W. Noble,et al.  Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. , 2009, Trends in molecular medicine.

[41]  Dmitri I Svergun,et al.  Domain conformation of tau protein studied by solution small-angle X-ray scattering. , 2008, Biochemistry.

[42]  Y. Liou,et al.  Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy. , 2008, The Journal of clinical investigation.

[43]  Ram Dixit,et al.  Differential Regulation of Dynein and Kinesin Motor Proteins by Tau , 2008, Science.

[44]  R. Tanzi,et al.  The 5′-untranslated region of Parkinson's disease α-synuclein messengerRNA contains a predicted iron responsive element , 2007, Molecular Psychiatry.

[45]  S. Andrieu,et al.  Wandering Behavior and Alzheimer Disease. The REAL.FR Prospective Study , 2007, Alzheimer disease and associated disorders.

[46]  H. Paudel,et al.  Cyclin-dependent protein kinase 5 primes microtubule-associated protein tau site-specifically for glycogen synthase kinase 3beta. , 2006, Biochemistry.

[47]  K. Matsubara,et al.  Aging and oxidative stress in progressive supranuclear palsy , 2006, European journal of neurology.

[48]  J. Kordower,et al.  Substantia nigra tangles are related to gait impairment in older persons , 2006, Annals of neurology.

[49]  Amy Chan,et al.  Dietary and genetically-induced oxidative stress alter tau phosphorylation: influence of folate and apolipoprotein E deficiency. , 2006, Journal of Alzheimer's disease : JAD.

[50]  N. Greig,et al.  Metal specificity of an iron-responsive element in Alzheimer's APP mRNA 5'untranslated region, tolerance of SH-SY5Y and H4 neural cells to desferrioxamine, clioquinol, VK-28, and a piperazine chelator. , 2006, Journal of neural transmission. Supplementum.

[51]  M. Núñez,et al.  Effect of iron on the activation of the MAPK/ERK pathway in PC12 neuroblastoma cells. , 2006, Biological research.

[52]  K. Ashe,et al.  Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L) , 2005, The Journal of Neuroscience.

[53]  B. Hyman,et al.  Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function , 2005, Science.

[54]  M. Polymeropoulos,et al.  Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene , 2005, Acta Neuropathologica.

[55]  W. Markesbery,et al.  Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. , 2005, Journal of Alzheimer's disease : JAD.

[56]  C. White,et al.  Downregulation of Protein Phosphatase 2A Carboxyl Methylation and Methyltransferase May Contribute to Alzheimer Disease Pathogenesis , 2004, Journal of neuropathology and experimental neurology.

[57]  I. Grundke‐Iqbal,et al.  Promotion of Hyperphosphorylation by Frontotemporal Dementia Tau Mutations* , 2004, Journal of Biological Chemistry.

[58]  G. Kontoghiorghes,et al.  The design and development of deferiprone (L1) and other iron chelators for clinical use: targeting methods and application prospects. , 2004, Current medicinal chemistry.

[59]  R. Maccioni,et al.  Iron-induced oxidative stress modify tau phosphorylation patterns in hippocampal cell cultures , 2003, Biometals.

[60]  Khadija Iqbal,et al.  Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia , 2004, Acta Neuropathologica.

[61]  R. Galanello,et al.  Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. , 2003, Blood.

[62]  Kazuyuki Takata,et al.  Cdk5 Is a Key Factor in Tau Aggregation and Tangle Formation In Vivo , 2003, Neuron.

[63]  Hironobu Naiki,et al.  Iron (III) induces aggregation of hyperphosphorylated τ and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer's disease , 2002 .

[64]  I. Ferrer,et al.  Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration , 2002, Acta Neuropathologica.

[65]  J. Trojanowski,et al.  Concurrence of α-synuclein and tau brain pathology in the Contursi kindred , 2002, Acta Neuropathologica.

[66]  R. Hider,et al.  Design of clinically useful iron(III)‐selective chelators , 2002, Medicinal research reviews.

[67]  B Miller,et al.  Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. , 2001, Archives of neurology.

[68]  I. Ferrer,et al.  Phosphorylated Map Kinase (ERK1, ERK2) Expression is Associated with Early Tau Deposition in Neurones and Glial Cells, but not with Increased Nuclear DNA Vulnerability and Cell Death, in Alzheimer Disease, Pick's Disease, Progressive Supranuclear Palsy and Corticobasal Degeneration , 2001, Brain pathology.

[69]  M Gallorini,et al.  Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes , 2001, Journal of neurochemistry.

[70]  Mark A. Smith,et al.  In Situ Oxidative Catalysis by Neurofibrillary Tangles and Senile Plaques in Alzheimer’s Disease , 2000, Journal of neurochemistry.

[71]  P. Davies,et al.  The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein , 1999, Nature.

[72]  D. Geschwind,et al.  Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[73]  Khadija Iqbal,et al.  Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. , 1998, Archives of biochemistry and biophysics.

[74]  B. Winblad,et al.  Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer's disease neurofibrillary degeneration , 1998, Brain Research.

[75]  J. Valpuesta,et al.  Ferritin is associated with the aberrant tau filaments present in progressive supranuclear palsy. , 1998, The American journal of pathology.

[76]  G. Perry,et al.  Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[77]  M. Beal,et al.  Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia , 1997, Annals of neurology.

[78]  E. Mandelkow,et al.  Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. , 1994, The Journal of biological chemistry.

[79]  C. Orvig,et al.  Complexation of iron with the orally active decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone). , 1992, Clinical chemistry.

[80]  J. Connor,et al.  A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains , 1992, Journal of neuroscience research.

[81]  D. McLachlan,et al.  Intramuscular desferrioxamine in patients with Alzheimer's disease , 1991, The Lancet.

[82]  P. Davies,et al.  A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[83]  K. Jellinger,et al.  Brain iron and ferritin in Parkinson's and Alzheimer's diseases , 1990, Journal of neural transmission. Parkinson's disease and dementia section.

[84]  A. Frankfurter,et al.  The distribution of tau in the mammalian central nervous system , 1985, The Journal of cell biology.

[85]  R. Morris.  Developments of a water-maze procedure for studying spatial learning in the rat , 1984, Journal of Neuroscience Methods.

[86]  A. Jacobs,et al.  An intracellular transit iron pool. , 2008, Ciba Foundation symposium.