MiP2005 - Young Investigator Presentation

Mitochondrial Physiology Network 10.9: 42 (2005) - download pdf


Mitochondrial abnormalities in a PC12 cell model of Alzheimer’s disease.

Kathrin L Schulz1, U Keil1, A Bonert1, WE Müller1, A Eckert2

1Inst. Pharmacology, Dept. Pharmaceutical Science, ZAFES Member, University of Frankfurt, Germany; 2Neurobiology Laboratory, University Psychiatric Hospitals, Basel, Switzerland. - KathrinSchulz@gmx.net

    Mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer’s Disease (AD) and other neurodegenerative disorders. The histopathological hallmarks of AD are extracellular senile plaques, consisting mainly of amyloid beta (Aß) peptide, and intracellular neurofibrillary tangles (NFT), consisting of hyperphosphorylated tau protein. Other characteristics are oxidative stress, diminished brain metabolism, reduced synaptic density, chronic inflammation and neuronal loss in selected brain regions. Today it is still unknown, whether intracellular or extracellular Aß is responsible for the oxidative stress-induced neurotoxic effects on mitochondria [1]. It also might be possible that an altered distribution of APP in subcellular compartments plays a crucial role for enhanced oxidative stress in the AD brain.

    We investigated the chronic effects of the Swedish double mutation in the beta amyloid precursor protein (APP) (APPsw) and human wildtype APP (APPwt) on mitochondrial function and acute effects of supplementary stress (Aß1-42, ER and oxidative stress) on mitochondrial calcium ([Ca2+]m) and mitochondrial membrane potential (Δψm) in PC12 cells. We determined the APP expression, Aß production and secretion into the extracellular compartment under basal conditions. APPwt and APPsw PC12 cells express the same amount of APP, but Aß production and secretion is 3-5 fold increased in APPsw PC12 cells due to the mutation [2]. Then, we investigated the chronic effects of APP and Aß on mitochondria and found no differences on basal [Ca2+]m. But the APPsw cells exhibit a significant reduced Δψm compared to wt and vector PC12 cells. We also found reduced ATP levels and reduced cytochrome c oxidase activity. Acute stimulation with secondary insults showed only small effects on [Ca2+]m, but distinct changes in Δψm especially on APPsw cells. Only stimulation with Thapsigargin led to a significant enhanced calcium uptake into the mitochondria in APPsw cells. Our findings support the hypothesis that APP or Aß might affect the mitochondrial calcium homeostasis and energy metabolism in a way, which enhanced the vulnerability of the cells for oxidative stress and other secondary insults during AD.

1.  Eckert A, Keil U, Marques CA, Bonert A, Frey C, Schussel K, Muller WE (2003) Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease, Biochem. Pharmacol. 66: 1627-1634.

2.  Marques CA, Keil U, Bonert A, Steiner B, Haass C, Muller WE, Eckert A (2003) Neurotoxic mechanisms caused by the Alzheimer's disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway. J. Biol. Chem. 278: 28294-28302.

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Mitochondrial Physiology