A circadian biological clock coordinates a variety of physiological processes in order to schedule them to the optimal time of day thereby synchronizing metabolism to periodically changing external conditions. Whereas accumulating evidence underscores the importance of the clock in physiological processes, almost nothing is known about clock function at the molecular level under pathophysiological conditions. This could be a significant factor e.g. in Alzheimer’s disease (AD), the most frequent dementia among the elderly. AD is characterized by neuropathological hallmarks of extracellular amyloid plaques (composed of the amyloid-beta (Abeta) protein) and intracellular neurofibrillary tangles (composed of hyperphosphorylated tau protein) in the brains of patients. It is known that the progression of cognitive impairment in AD patients is paralleled by an increasing occurrence of circadian disturbances. Of note, alterations of the circadian rhythm can be observed already in patients at early AD stages which may exhibit an increased sleep propensity during daytime with hyperactivity and agitation occurring in the evening hours (“sundowning syndrome”). These changes are postulated to result from an impairment of the endogenous circadian oscillator. Since they are already present in mild AD, it can be hypothesized that early-stage AD events such as tau hyperphosphorylation and Abeta aggregation might have an effect on circadian rhythm. Accumulating evidence indicates alterations in mitochondrial function intracellular energy levels, increased oxidative stress, as well as changes in antioxidant defence. Although the majority of currently available experimental evidence supports the hypothesis that oxidative stress pathways play a crucial role in AD, conflicting results have been reported in this context. The provided findings are only representative for one random time point of investigation so far, but nothing is known about possible circadian oscillations. However, the latter is of particular interest as the intracellular redox machinery involves many components, and even minor imbalances can cause dramatic effects. This currently lacking evidence might also at least partly explain the inconsistencies of some reported findings. Our project is specifically designed to i) Study the possible link between dynamics of mitochondria and circadian rhythm of energy metabolism. By performing the suggested experiments, we will gain first evidence on whether the AD-related proteins Abeta and hyperphosphorylated tau influence the dynamic changes of mitochondrial morphology and whether these changes are subject to modulation by circadian rhythms. ii) Study the expression of mitochondrially and nuclearly encoded genes and/or proteins involved in mitochondrial function and regulated by circadian rhythm. Based on the fact that several mitochondria-related genes display a circadian expression pattern, we expect changes in the expression pattern of crucial genes and proteins, e.g. subunits of the respiratory chain complexes and detoxifying enzymes, in our cell models modulated by Abeta and/or tau.