Mutations in tau fan the flames of Alzheimer’s, Parkinson’s, and other tauopathies. What is tau doing that gets it mixed up in so many neurodegenerative conditions? Could the answer lie not in the tangles that besmirch the brains of affected individuals, but in tau’s failure to perform a newly discovered role: promoting iron export? Ashley Bush and colleagues at the University of Melbourne in Australia report in the January 29 Nature Medicine online that without tau, amyloid precursor protein (APP) is unable to reach neurons’ surfaces, where it is needed to work the bellows that pump excess iron out of the cell. Mice missing tau develop symptoms akin to the Parkinson’s-dementia complex that afflicts many people with PD, Bush said. A gentle chelator that sops up the extra iron cures them, suggesting a potential route to treat not only Parkinson’s, but also Alzheimer’s and other conditions, Bush claims.

Tau is a microtubule-binding protein believed to support axonal traffic—but researchers are not sure what kind of cargo might be most important. “We think it is APP,” Bush said. “We feel this is the strongest evidence that the problem [in Parkinson’s] is the loss of iron homeostasis.” Cells need iron, but not too much since it can participate in the formation of dangerous free radicals. Iron is also found in amyloid plaques and tau tangles (Smith et al., 1997). Bush has been chasing the question of metal malfunction in neurodegeneration for years, systematically scouring Alzheimer’s proteins for a potential role in metal management. His group implicated presenilins in cellular uptake of zinc and copper (Greenough et al., 2011) and APP in iron export (see ARF related news story on Duce et al., 2010). In the current paper, first author Peng Lei and colleagues focused on tau but ended up extending APP’s function in iron metabolism beyond Alzheimer’s and into Parkinson’s, noted Jack Rogers of Massachusetts General Hospital in Boston, who was not involved with this study but has collaborated with Bush in the past.

Although tau knockout mice have been around for a decade, they have no neurodegeneration (Dawson et al., 2001). However, scientists had not looked beyond seven months, Bush said. Lei and colleagues decided to wait until the animals reached a year old. “Lo and behold, 12 months onward their brains fall to pieces,” Bush said.

At one year, the brains of tau knockout mice weighed less than wild-type mouse brains of the same age, and their neocortex and cerebellar cortex were atrophied. They also had fewer dopaminergic neurons in the substantia nigra and performed poorly on locomotor tests. Most relevant to Lei and Bush’s interests, the mice accumulated iron in the cortex, hippocampus, and substantia nigra, and treatment with the Parkinson’s drug L-dopa reversed the motor symptoms.

The aged tau knockout mice represent an interesting new model for PD, commented Julie Andersen of the Buck Institute for Research on Aging in Novato, California, who was not involved with the paper. The model is a chronic, age-related condition, unlike the commonly used acute parkinsonism model caused by the chemical MPTP. On the con side, she added that the neurodegeneration seems to involve less dopaminergic neuron loss than human Parkinson’s, and it occurs not only in the substantia nigra, but also in the ventral tegmental area. “It is not perfect,” she said, “but then, no mouse model for neurodegeneration is.”

Could iron and tau be connected in people? Lei examined brain tissue from people who died with Parkinson’s and detected less soluble tau, but more iron, in their substantia nigras than in the same region from age-matched controls. Other scientists have observed lowered tau concentrations in the tauopathies Alzheimer’s and frontotemporal dementia (Ksiezak-Reding et al., 1988; Zhukareva et al., 2003).

The group has been extensively testing the metal-chelating drug clioquinol as a therapeutic. Bush and Andersen used it to protect against MPTP-induced symptoms in mice (see ARF related news story on Kaur et al., 2003), and Bush and colleagues used it to bust plaques in AD model mice (see ARF related news story on Cherny et al., 2001) and treat people with AD in a pilot study (see ARF related news story on Ritchie et al., 2003). Added to mouse chow, clioquinol blocked iron accumulation, neurodegeneration, and Parkinson’s-like symptoms seen in untreated tau-deficient mice as they aged. “It worked brilliantly,” Bush said.

The inverse relationship between iron and tau reminded the researchers of their discoveries with APP and iron. They used primary cortical neurons from the tau knockout strain to look for effects on APP. Although the tau-negative neurons contained plenty of APP, it failed to mature and reach the cell surface. The knockout neurons accumulated iron and were sensitive to iron toxicity. The findings suggest that tauopathies might not only be caused by a gain of toxic function due to neurofibrillary tangles, but also a loss of tau’s natural function in iron homeostasis, Andersen said. “APP, tau, etc., play a critical physiological role,” said George Perry of the University of Texas at San Antonio, who was not involved with the study. “Those processes are really part of how cells regulate themselves normally.”

The paper “adds to the evidence that iron accumulation, which continues into old age, may be part of the ‘age’ component of age-related neurodegenerative diseases such as AD, PD, and HD, and also why men (who have higher brain iron levels than women) may get these diseases earlier than women,” wrote George Bartzokis of the University of California, Los Angeles, in an e-mail to ARF (Bartzokis et al., 2007). Bartzokis was not involved in the study.

Returning iron levels to normal, Bush thinks, should be therapeutic. Prana Biotechnology Limited in Parkville, Australia, a company Bush co-founded but is no longer associated with, has tested a second-generation clioquinol-like compound called PBT2 in Alzheimer’s, and is starting a Huntington’s trial. In addition, Rogers warned that researchers developing therapies targeted at APP or tau might want to monitor effects on iron metabolism.—Amber Dance

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  1. This paper by Lei et al. provides two important novel observations. Firstly, as a parkinsonian model, the tau knockout mice are exciting because they do not show symptoms of disease until 12 months of age; thus, similar to Parkinson’s patients, there is an age dependency for symptom onset and presumably host vulnerability. Secondly, the data demonstrate that tau itself is not the culprit but an age-dependent accumulation of iron because tau has been absent from birth in the mice but symptom onset is not until iron levels reach a threshold level. Therefore, the role of iron in the pathogenesis of Parkinson's becomes even stronger. Moreover, the data continue to implicate amyloid-β precursor protein (APP) in the neuronal regulation of iron; although one can wonder why, given the reported importance of APP as a neuronal exporter of iron, it would take 12 months for enough iron to accumulate to see an effect. It would be informative to know the expression of ferritin in the neurons. Ferritin could offer protection from the iron by sequestering it. A number of years ago we had argued that it is not iron that is problematic for cells, but the mismanagement of iron, including in Parkinson’s brains (Connor et al., 1995). The accumulation of ferritin could be expected to have limited impact in acute models of tyrosine hydroxylase neuronal degeneration in response to toxin injections, but in a chronic model, as in the tau knockout mice of Lei et al., a failure of ferritin expression and protection could provide insights into how iron accumulation is problematic. Loss of ferritin may also explain why the cells do not respond better to the iron accumulation by protecting themselves and provide potential targets for therapy. If ferritin could be induced, would it be protective in this model? It was shown that expression of ferritin in tyrosine hydroxylase neurons protects them from MPTP (Kaur et al., 2003). Maybe the cells do express ferritin, but over time the amounts of ferritin become insufficient to offer protection.

    The tau knockout animal model could also be valuable in providing MRI data that could help answer when, in the time frame of symptom onset, iron accumulation in the SN begins. This is important, since the clioquinol was given beginning at 6.5 months for five months. It is remarkable that over the length of time this drug was present, there was no loss of liver iron, or that neither copper nor zinc levels were affected by this drug.

    This study joins a number of others on various degenerative diseases or models such as stroke, ALS, and multiple sclerosis in demonstrating that providing an iron chelator prior to the onset of damage or disease was protective. Thus, there is a long line of evidence that limiting iron is beneficial. The challenge ahead is to determine if the iron reverses or rescues symptoms similar to the single dose of L-DOPA. For now, we have a new, exciting animal model that continues to support the findings that APP has important ferroxidase activity in the brain, and that mutations in proteins as important as tau require additional factors, such as iron accumulation, to induce neurodegeneration. The data also strongly argue that iron is pathogenic in PD and not a bystander effect secondary to neurodegeneration.

    References:

    . A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains. J Neurochem. 1995 Aug;65(2):717-24. PubMed.

    . Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron. 2003 Mar 27;37(6):899-909. PubMed.

    View all comments by James R. Connor

References

News Citations

  1. Iron Export? New Role Links APP, Metals, to Oxidative Stress
  2. Ironing out the Role of Metals in Neurodegenerative Diseases
  3. Two Ways to Attack Amyloid: Metal Chelator and Antibody
  4. Pilot Study Suggests Clioquinol Benefits AD Patients

Paper Citations

  1. . Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9866-8. PubMed.
  2. . Presenilins promote the cellular uptake of copper and zinc and maintain copper chaperone of SOD1-dependent copper/zinc superoxide dismutase activity. J Biol Chem. 2011 Mar 18;286(11):9776-86. PubMed.
  3. . Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010 Sep 17;142(6):857-67. PubMed.
  4. . Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci. 2001 Mar;114(Pt 6):1179-87. PubMed.
  5. . Immunochemical and biochemical characterization of tau proteins in normal and Alzheimer's disease brains with Alz 50 and Tau-1. J Biol Chem. 1988 Jun 15;263(17):7948-53. PubMed.
  6. . Selective reduction of soluble tau proteins in sporadic and familial frontotemporal dementias: an international follow-up study. Acta Neuropathol. 2003 May;105(5):469-76. PubMed.
  7. . Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron. 2003 Mar 27;37(6):899-909. PubMed.
  8. . Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001 Jun;30(3):665-76. PubMed.
  9. . Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003 Dec;60(12):1685-91. PubMed.
  10. . Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol Aging. 2007 Mar;28(3):414-23. PubMed.

External Citations

  1. PBT2
  2. Huntington’s trial

Further Reading

Papers

  1. . Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. Int J Dev Neurosci. 2000 Jul-Aug;18(4-5):433-7. PubMed.
  2. . Neuronal CDK7 in hippocampus is related to aging and Alzheimer disease. Neurobiol Aging. 2000 Nov-Dec;21(6):807-13. PubMed.
  3. . Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. 1994 Jun 9;369(6480):488-91. PubMed.
  4. . Metals in alzheimer's disease: a systemic perspective. Front Biosci. 2012;17:451-72. PubMed.
  5. . Different 8-Hydroxyquinolines Protect Models of TDP-43 Protein, α-Synuclein, and Polyglutamine Proteotoxicity through Distinct Mechanisms. J Biol Chem. 2012 Feb 3;287(6):4107-20. PubMed.
  6. . Copper in the brain and Alzheimer's disease. J Biol Inorg Chem. 2010 Jan;15(1):61-76. PubMed.
  7. . Targeting multiple Alzheimer's disease etiologies with multimodal neuroprotective and neurorestorative iron chelators. FASEB J. 2008 May;22(5):1296-305. PubMed.
  8. . The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimer's disease. FEBS J. 2007 Aug;274(15):3775-83. PubMed.
  9. . Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett. 2000 Feb 4;279(3):129-32. PubMed.

Primary Papers

  1. . Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012 Feb;18(2):291-5. PubMed.