MiP2005: Session 9 - Young Investigator Presentation
Mitochondrial Physiology Network 10.9: 103-104 (2005) - download pdf
APP transgenic mice exhibit mitochondrial dysfunction.
Susanne Hauptmann1, I Scherping1, U Keil1, A Eckert1,2, WE Müller1
1Dept. Pharmacology, Biocentre, University of Frankfurt, 60439 Frankfurt, Germany; 2Neurobiology Research Laboratory, Psychiatric University Clinic, 4025 Basel, Switzerland. - email@example.com
Mitochondrial dysfunction underlies many common age-related diseases, including Alzheimer’s disease (AD). AD is characterized by two major histopathological hallmarks, extracellular plaques of fibrillar ß-amyloid (Aß) peptides and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein [1,2]. In previous studies we could show that P301L tau transgenic mice exhibit mitochondrial respiratory defects . Furthermore, accumulation of Aß and oxidative stress seem to play central roles in the pathogenesis, by probably directly leading to mitochondrial dysfunction.
To investigate the contribution of Aß in AD-related neurodegenerative processes, we used isolated mitochondria of APP transgenic (tg) mice. These mice exhibits onset of Aß plaques at an age of 6 months, but intracellular Aß load is already increased at the age of 3 months. The non-physiological high levels of Aß found in transgenic mice lead to senile plaque formation like in their human counterparts, preceded by oxidative stress . We detected decreased basal levels of mitochondrial membrane potential (Δψm) in tgAPP mice compared to littermate non-tg control mice. Hydrogen peroxide and the nitric oxide donor sodium nitroprussid damaged the cells significantly by decreasing Psim in littermate non-tg control mice but not in tgAPP mice. Most probably, this is due to the preliminary insult caused by the chronic APP exposure. In addition, we observed decreased ATP levels behaving in a similar pattern after additional oxidative stress. Complementary, we observed a significant reduction of cytochrome c oxidase activity in 8 month old tg APP mice. In contrast, no differences in the NADH ubiquinone oxidoreductase activity between WT and tgAPP mice could be observed.
Our results further emphazise the important role of mitochondrial dysfunction in the pathogenesis of AD. Moreover, they indicate that Aß is already involved in these neurotoxic mechanisms before plaque formation occurs.
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