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1 Acta Neurobiologiae Experimentalis

1 2013

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Alzheimer’s amyloid beta peptides disturb circadian oscillations of intracellular calcium concentration

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Kazmierczak A. , Schmitt K. , Grimm A. , Strosznajder J. B. , Eckert A.

nr 1

It is postulated that disturbances in calcium homeostasis play an important role in pathogenesis of Alzheimer’s disease (AD). Changes of neuronal calcium concentration are responsible for the oxidative stress as well as altered metabolism and production of amyloid-beta peptides (Aβ). Aβ may further exacerbate calcium dysregulation, causing synaptic dysfunction, neurodegeneration and cognitive impairment. Recent data indicate that AD is associated with disturbances of circadian rhythm in the patients. However, till now nothing is known about the molecular mechanisms involved in AD-related circadian clock alterations. In our study we investigated the effect of Aβ peptides on the rhythmic oscillation of cytosolic and mitochondrial calcium levels. To investigate molecular clock mechanisms, the studies we carried out in human primary skin fibroblasts, a previously established experimental model. Our data showed circadian rhythm of calcium ions concentration in cytosol and mitochondria. Moreover we observed circadian oscillation of ROS formation and redox potential. Treatment with Aβ fibrils at the concentration of 0.5 µM disturbed cytosolic calcium oscillations and mitochondrial redox state. Studying mechanisms involved in this phenomenon indicated that Aβ did not affect ER calcium stores, but induced changes of calcium influx mediated by purinergic P2X7 receptor. The specific antagonist of P2X7 receptor Brillant Blue G abolished negative impact of Aβ and restored calcium circadian rhythm. Summarizing, our results indicate that Aβ may play a significant role in disturbances of circadian calcium oscillation, suggesting the importance of this phenomenon in ADrelated changes in biological clock. Supported by grants from Sciex 10. 258 to A.K. as well as Swiss National foundation (SNF No 310030_122572) and Synapsis Foundation to A.E.