Proteomic and Functional Analyses Reveal a Mitochondrial Dysfunction in P301L Tau Transgenic Mice

doi:10.1074/jbc.M500356200

Proteomic and Functional Analyses Reveal a Mitochondrial Dysfunction in P301L Tau Transgenic Mice*

^‡Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland, and ^§Department of Pharmacology, Biocentre, University of Frankfurt, 60439 Frankfurt, Germany, ^∥Department of Human Genetics, Section of Medical Genomics and Center for Neurogenomics and Cognitive Research, VU University Medical Center and VU University, 1081 BT Amsterdam, The Netherlands, ^**The Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands, ^‡‡Center for Biological Chemistry, University of Frankfurt, 60590 Frankfurt, Germany, and ^§§Neurobiology Research Laboratory, Psychiatric University Clinic, 4025 Basel, Switzerland

¶¶ To whom correspondence should be addressed: Brain and Mind Research Institute, University of Sydney, 100 Mallet St., Camperdown, NSW 2050, Australia. Tel.: 61-2-9351-0799; Fax: 61-2-9351-0652; E-mail: jgoetz{at}med.usyd.edu.au.

Abstract

Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dys-function was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward β-amyloid (Aβ) peptide insult, suggesting a synergistic action of tau and Aβ pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Aβ.

Footnotes

↵1 The abbreviations used are: AD, Alzheimer disease; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; NFT, neurofibrillary tangle; Aβ, β-amyloid; WT, wild-type; ROS, reactive oxygen species; GST, glutathione S-transferase; SOD, superoxide dismutase; GR, glutathione reductase; DRP, dihydropyrimidinase-related protein; MALDI, matrix-assisted laser desorption ionization; TOF/TOF, tandem time-of-flight; MDA, malondialdehyde; DBQ, n-decylubiquinone; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HAR, hexaammineruthenium(III)-chloride; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; DHE, dihydroethidium; H₂DCF-DA, 2′,7′-dichlorodihydrofluorescein diacetate; PIPES, 1,4-piperazinediethanesulfonic acid; MOPS, 4-morpholinepropanesulfonic acid; ANOVA, analysis of variance; IPG, immobilized pH gradient.
↵* This work was supported by grants from the EMDO Foundation, the Olga Mayenfisch Foundation, the Kurt und Senta Herrmann Foundation, the National Centers of Competence in Research on Neural Plasticity and Repair, and the Swiss National Science Foundation (to J. G.); Swiss National Science Foundation (to A. E.); Deutsche Forschungsgemeinschaft Grant SFB 472-P2 (to U. B.); and a grant from Hirnliga e.V. (to U. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¶ Both authors contributed equally to this work.
- Received January 11, 2005.
- Revision received April 13, 2005.
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