Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice

Hauptmann, S.; Scherping, I.; Dröse, S.; Brandt, U.; Schulz, K.L.; Jendrach, M.; Leuner, K.; Eckert, A.; Müller, W.E.

doi:10.1016/j.neurobiolaging.2007.12.005

« Previous Next »Neurobiology of Aging
Volume 30, Issue 10 , Pages 1574-1586, October 2009

Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice

S. Hauptmann
- Department of Pharmacology, ZAFES, Biocenter, University of Frankfurt, 60438 Frankfurt, Germany
- Both authors contributed equally to this work.
I. Scherping
- Department of Pharmacology, ZAFES, Biocenter, University of Frankfurt, 60438 Frankfurt, Germany
- Both authors contributed equally to this work.
S. Dröse
- Molecular Bioenergetics Group, Medical School, Centre of Excellence Frankfurt “Macromolecular Complexes”, University of Frankfurt, Theodor Stein Kai 7, 60590 Frankfurt/M., Germany
U. Brandt
- Molecular Bioenergetics Group, Medical School, Centre of Excellence Frankfurt “Macromolecular Complexes”, University of Frankfurt, Theodor Stein Kai 7, 60590 Frankfurt/M., Germany
K.L. Schulz
- Department of Pharmacology, ZAFES, Biocenter, University of Frankfurt, 60438 Frankfurt, Germany
M. Jendrach
- Kinematic Cell Research Group, Institute for Cell Biology and Neuroscience, JW Goethe University, Max-von-Laue-Strasse 9, D-60438 Frankfurt/Main, Germany
K. Leuner
- Department of Pharmacology, ZAFES, Biocenter, University of Frankfurt, 60438 Frankfurt, Germany
A. Eckert
- Neurobiology Research Laboratory, Psychiatric University Clinic, 4025 Basel, Switzerland
W.E. Müller
- Department of Pharmacology, ZAFES, Biocenter, University of Frankfurt, 60438 Frankfurt, Germany
- Corresponding author. Tel.: +49 6979829373; fax: +49 6979829374.

Received 25 January 2007; received in revised form 3 December 2007; accepted 5 December 2007. published online 27 February 2008.

Abstract

Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer's disease integrating genetic factors related to enhanced amyloid-beta (Aß) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and Aß pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular Aß deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular Aß. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that Aß dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of Aß and progression accelerates substantially with aging.

Keywords: Alzheimer's disease, APP mutation, Aging