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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-49902

David, D C; Hauptmann, S; Scherping, I; Schuessel, K; Keil, U; Rizzu, P; Ravid, R; Dröse, S; Brandt, U; Müller, W E; Eckert, A; Götz, J (2005). Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. Journal of Biological Chemistry, 280(25):23802-23814.

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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 beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Division of Psychiatric Research and Clinic for Psychogeriatric Medicine
DDC:610 Medicine & health
Language:English
Date:2005
Deposited On:18 Oct 2011 08:30
Last Modified:08 Dec 2013 03:12
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1074/jbc.M500356200
PubMed ID:15831501
Citations:Web of Science®. Times Cited: 139
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Scopus®. Citation Count: 156

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