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

Lei, Peng, Ayton, Scott, Finkelstein, David I., Spoerri, Loredana, Ciccotosto, Giuseppe D., Wright, David K., Wong, Bruce X. W., Adlard, Paul A., Cherny, Robert A., Lam, Linh Q., Roberts, Blaine R., Volitakis, Irene, Egan, Gary F., McLean, Catriona A., Cappai, Roberto, Duce, James A. and Bush, Ashley I. (2012) Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nature Medicine, 18 2: 291-295. doi:10.1038/nm.2613

Author Lei, Peng
Ayton, Scott
Finkelstein, David I.
Spoerri, Loredana
Ciccotosto, Giuseppe D.
Wright, David K.
Wong, Bruce X. W.
Adlard, Paul A.
Cherny, Robert A.
Lam, Linh Q.
Roberts, Blaine R.
Volitakis, Irene
Egan, Gary F.
McLean, Catriona A.
Cappai, Roberto
Duce, James A.
Bush, Ashley I.
Title Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export
Journal name Nature Medicine   Check publisher's open access policy
ISSN 1078-8956
Publication date 2012-02
Sub-type Article (original research)
DOI 10.1038/nm.2613
Open Access Status
Volume 18
Issue 2
Start page 291
End page 295
Total pages 5
Place of publication New York, United States
Publisher Nature
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
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Created: Fri, 30 May 2014, 13:55:21 EST by Loredana Spoerri on behalf of UQ Diamantina Institute