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Combined expression of tau and the Harlequin mouse mutation leads to increased mitochondrial dysfunction, tau pathology and neurodegeneration

Kulic, Luka and Wollmer, M. Axel and Rhein, Virginie and Pagani, Lucia and Kuehnle, Katrin and Cattepoel, Susann and Tracy, Jay and Eckert, Anne and Nitsch, Roger M.. (2011) Combined expression of tau and the Harlequin mouse mutation leads to increased mitochondrial dysfunction, tau pathology and neurodegeneration. Neurobiology of aging, Vol. 32, H. 10. pp. 1827-1838.

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Official URL: http://edoc.unibas.ch/dok/A6004662

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Abstract

Mitochondrial dysfunction and oxidative stress play an important role in ageing and have been implicated in several age-related neurodegenerative conditions including Alzheimer's disease (AD) and other tauopathies characterized by the presence of intracellular accumulations of the hyperphosphorylated microtubule-associated protein tau. To study the interaction between mitochondrial dysfunction and tau pathology in vivo, we generated a novel mouse model by crossbreeding two existing lines: the Harlequin (Hq) mutant mice which suffer from mitochondrial dysfunction and oxidative stress due to a lack of the mitochondrial apoptosis-inducing factor (AIF), and the P301L tau transgenic mice, a mouse model of human tau pathology. Combined expression of the Hq mouse mutation and the tau transgene in the Tau/Hq double mutant mice led to an increase in tau pathology and apoptotic neurodegeneration when compared to single expression of the two mutations. Neurodegeneration was most prominent in the dentate gyrus and was significantly increased in the cerebellum leading to aggravated motor deficits. Functional activity measurements of the mitochondrial respiratory chain (MRC) in the Tau/Hq mice revealed early decreased activities of multiple MRC complexes and depleted ATP levels which preceded neurodegeneration and elevated oxidative stress markers. These results suggest an age-dependent mutual reinforcement of the tau pathology and mitochondrial dysfunction in vivo, which may contribute to neurodegeneration in patients suffering from AD and other age-related tauopathies.
Faculties and Departments:03 Faculty of Medicine > Bereich Psychiatrie (Klinik) > Erwachsenenpsychiatrie UPK > Erwachsenenpsychiatrie (Lang)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Psychiatrie (Klinik) > Erwachsenenpsychiatrie UPK > Erwachsenenpsychiatrie (Lang)
UniBasel Contributors:Eckert, Anne
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier Science
ISSN:0197-4580
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:25 Oct 2013 08:32
Deposited On:25 Oct 2013 08:32

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