P2‐267: Mitochondrial dynamics in Alzheimer's disease

Mitochondrial dysfunction is a hallmark of amyloid-beta (Aß)-induced neuronal toxicity in Alzheimer's disease (AD). Aß triggers mitochondrial dysfunction through several pathways, such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production and alteration of mitochondrial dynamics. Particularly, the control and maintenance of mitochondrial dynamics requires a tightly regulated equilibrium between opposing mitochondrial fusion and fission activities. Importantly, disturbances of fusion and fission activities or their imbalance result in mitochondrial impairment that might play a crucial role in neurodegeneration. The aim of this study is to better understand the key role of mitochondrial dynamics in AD. For this purpose, we first characterized the mitochondrial network by confocal microscope in cell cycle-controlled human primary skin fibroblasts. Then, we analysed the expression levels of mitochondrial fusion (MFN1, MFN2, and OPA1) and fission (DNML1, Fis1) genes and the expression of ascertained genes involved in the mitochondrial respiration. We found that the mitochondrial network is characterized by 3 distinct states (fragmented, intermediate and tubular), during one cell cycle. Our preliminary data show that the expression of mitochondrial fusion genes is enhanced in the tubular mitochondrial network whereas expression of mitochondrial fission genes does not change between tubular and fragmented mitochondrial network. In addition, an increase of the expression of complex V subunits involved in ATP production was observed in fragmented mitochondrial network but mot in tubular network. Plus, in between the switch of tubular to fragmented mitochondrial network, we observed a transient increase in ATP level. Currently, we investigate changes induced by Aß in the regulation of mitochondrial dynamics and energy homeostasis. We expect from these experiments new insights into the vicious cycle between abnormal mitochondrial dynamics, mitochondrial function and energy production in AD. Acknowledgements: This work was supported by grants from the Swiss National Science Foundation (#31000_122572) and Synapsis Foundation.