Cell clocks and neuronal networks: neuron ticking and synchronization in aging and aging-related neurodegenerative disease.

Body function rhythmicity has a key role in the regulation of internal timing and adaptation to the environment. A wealth of recent data has implicated endogenous biological rhythm generation and regulation in susceptibility to disease, longevity, cognitive performance. It has been established that many molecular pathways implicated in neurodegeneration are under circadian regulation. At the molecular level, the regulation of circadian rhythms relies on clock genes forming interconnected, self-sustained transcriptional/translational feedback loops. Cells of the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus, are endowed with this molecular clockwork. Brain cells in many other regions, including those that play a key role in learning and memory, as well as peripheral cells show a circadian oscillatory behavior regulated by the same molecular clockwork. We here address the question as to whether intracellular clockwork signaling and/or the intercellular dialogue between “brain clocks” are disrupted in aging-dependent neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. The potential implications of clock genes in cognitive functions in normal conditions, clinical disturbances of circadian rhythms, and especially the sleep-wake cycle, in aging-dependent neurodegenerative diseases and data in animal models are reviewed. The currently limited knowledge in this field is discussed in the context of the more extensive body of data available on cell clocks and molecular clockwork during normal aging. Hypotheses on implications of the synchronization between brain oscillators in information processing in neural networks lay ground for future studies on cognitive functions and aging-related neurodegenerative diseases