Combined expression of tau and the Harlequin mouse mutation leads to increased mitochondrial dysfunction, tau pathology and neurodegeneration.
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.
Kulic
Luka
L
Division of Psychiatry Research, University of Zurich, August Forel Str. 1, 8008 Zurich, Switzerland. luka.kulic@bli.uzh.ch
Wollmer
M Axel
MA
Rhein
Virginie
V
Pagani
Lucia
L
Kuehnle
Katrin
K
Cattepoel
Susann
S
Tracy
Jay
J
Eckert
Anne
A
Nitsch
Roger M
RM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D053148:Caspase 3 / Q000378:metabolism; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D020287:In Situ Nick-End Labeling; D007930:Leucine / Q000235:genetics; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000235:genetics*; D009069:Movement Disorders / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011392:Proline / Q000235:genetics; D017494:Proton Pumps / Q000378:metabolism; D016622:Silver Staining / Q000379:methods; D018709:Statistics, Nonparametric; D024801:Tauopathies / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
D051033:Apoptosis Inducing Factor; D009419:Nerve Tissue Proteins; D017494:Proton Pumps; D016875:tau Proteins; D000255:Adenosine Triphosphate; D011392:Proline; D053148:Caspase 3; D042967:Electron Transport Complex I; D007930:Leucine