Search

Body function rhythmicity has a key function for 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. Concerning brain diseases, it has been established that many molecular pathways implicated in neurodegeneration are under circadian regulation. At the molecular level, this regulation 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 which 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 brain health and disease.

Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal models of neurodegenerative diseases. Such results were mainly associated with the epigenetic modulation caused by HDACs, especially those from class I, via chromatin deacetylation. However, other mechanisms may contribute to the neuroprotective effect of HDAC inhibitors, since each HDAC may present distinct specific functions within the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration has been partially elucidated so far. The strategy to be adopted in promising therapeutics targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection by increasing the acetylation levels of α-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders. On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders, including Alzheimer's, Parkinson's and Hutington's diseases. This review describes the specific role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by collecting in silico, in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover, structure, function, subcellular localization, as well as the level of HDAC6 expression within brain regions are reviewed and compared to the other HDAC isoforms. In various neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other proteins seem to be a promising approach in understanding the modulation of HDAC6 activity.

A bulk of studies in rodents and humans suggest that sleep facilitates different phases of learning and memory process, while sleep deprivation (SD) impairs these processes. Here we tested the hypothesis that SD could alter spatial learning and memory processing in a non-human primate, the grey mouse lemur (Microcebus murinus), which is an interesting model of aging and Alzheimer's disease (AD). Two sets of experiments were performed. In a first set of experiments, we investigated the effects of SD on spatial learning and memory retrieval after one day of training in a circular platform task. Eleven male mouse lemurs aged between 2 to 3 years were tested in three different conditions: without SD as a baseline reference, 8 h of SD before the training and 8 h of SD before the testing. The SD was confirmed by electroencephalographic recordings. Results showed no effect of SD on learning when SD was applied before the training. When the SD was applied before the testing, it induced an increase of the amount of errors and of the latency prior to reach the target. In a second set of experiments, we tested the effect of 8 h of SD on spatial memory retrieval after 3 days of training. Twenty male mouse lemurs aged between 2 to 3 years were tested in this set of experiments. In this condition, the SD did not affect memory retrieval. This is the first study that documents the disruptive effects of the SD on spatial memory retrieval in this primate which may serve as a new validated challenge to investigate the effects of new compounds along physiological and pathological aging. [ABSTRACT FROM AUTHOR]