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Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export

Nature Medicine volume 18, pages 291–295 (2012)Cite this article

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Abstract

The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies1,2,3,4. Aggregated tau forms neurofibrillary tangles in these pathologies3,5, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease6,7, the substantia nigra (SN) in Parkinson's disease8,9,10,11 and various brain regions in the tauopathies11,12. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation7. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies13,14,15, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.

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Figure 1: Tau loss is associated with the Parkinson's phenotype.
Figure 2: Age-dependent cognitive dysfunction in tau-KO mice.
Figure 3: Iron accumulation mediates age-dependent neurodegeneration in tau-KO mice.
Figure 4: Knockout of tau causes iron accumulation by preventing APP trafficking to the cell surface.

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Acknowledgements

This work was supported by funds from the Australian Research Council, the National Health & Medical Research Council of Australia (NHMRC) and the Alzheimer's Association. The Victorian Brain Bank Network is supported by The University of Melbourne, The Mental Health Research Institute, The Alfred Hospital and the Victorian Forensic Institute of Medicine, and funded by Neurosciences Australia and the NHMRC. The authors thank Y.-H. Hung, H. Kim, S.H. Bush and A. Sedjahtera for helpful discussion and technical assistance, H.N. Dawson (Duke University) for providing the tau-knockout mice, and T.A. Rouault and D.L. Zhang (US National Institutes of Health) for MAP23 antibody.

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  1. Gary F Egan

    Present address: Present address: Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia.,

Authors and Affiliations

  1. Mental Health Research Institute, The University of Melbourne, Victoria, Australia

    Peng Lei, Scott Ayton, David I Finkelstein, Giuseppe D Ciccotosto, Bruce X W Wong, Paul A Adlard, Robert A Cherny, Linh Q Lam, Blaine R Roberts, Irene Volitakis, James A Duce & Ashley I Bush

  2. Department of Pathology, The University of Melbourne, Victoria, Australia

    Peng Lei, Loredana Spoerri, Giuseppe D Ciccotosto, Paul A Adlard, Catriona A McLean, Roberto Cappai & Ashley I Bush

  3. Centre for Neuroscience, The University of Melbourne, Victoria, Australia

    Scott Ayton, David I Finkelstein & James A Duce

  4. Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, Australia

    Loredana Spoerri, Giuseppe D Ciccotosto & Roberto Cappai

  5. Florey Neuroscience Institutes, The University of Melbourne, Victoria, Australia

    David K Wright & Gary F Egan

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Contributions

P.L. and A.I.B. conceived of the study. A.I.B. raised funds for the study. P.L., S.A., J.A.D., L.S., D.K.W., P.A.A., D.I.F. and A.I.B. designed and performed the experiments. G.D.C., B.X.W.W., L.Q.L., B.R.R., I.V. and C.A.M. assisted with the experiments. G.F.E., P.A.A., R.A.C., R.C., D.I.F. and A.I.B supervised the experiments. P.L. and A.I.B. analyzed the data and wrote drafts of the manuscript. All authors edited the manuscript.

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Correspondence to Ashley I Bush.

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Competing interests

P.A.A., R.A.C., D.I.F. and A.I.B. are shareholders in and paid scientific consultants for Prana Biotechnology. A.I.B. is a shareholder in Eucalyptus and Cogstate and a consultant for Adeona Pharmaceuticals.

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Lei, P., Ayton, S., Finkelstein, D. et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 18, 291–295 (2012). https://doi.org/10.1038/nm.2613

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