Abstract
Ageing is an inevitable biological process that results in a progressive structural and functional decline, as well as biochemical alterations that altogether lead to reduced ability to adapt to environmental changes. As clock oscillations and clock-controlled rhythms are not resilient to the aging process, aging of the circadian system may also increase susceptibility to age-related pathologies such as Alzheimer's disease (AD). Besides the amyloid-beta protein (Aβ)-induced metabolic decline and neuronal toxicity in AD, numerous studies have demonstrated that the disruption of sleep and circadian rhythms is one of the common and earliest signs of the disease. In this study, we addressed the questions of whether Aβ contributes to an abnormal molecular circadian clock leading to a bioenergetic imbalance. For this purpose, we used different oscillator cellular models: human skin fibroblasts, human glioma cells, as well as mouse primary cortical and hippocampal neurons. We first evaluated the circadian period length, a molecular clock property, in the presence of different Aβ species. We report here that physiologically relevant Aβ1–42 concentrations ranging from 10 to 500 nM induced an increase of the period length in human skin fibroblasts, human A172 glioma cells as well as in mouse primary neurons whereas the reverse control peptide Aβ42-1, which is devoid of toxic action, did not influence the circadian period length within the same concentration range. To better understand the underlying mechanisms that are involved in the Aβ-related alterations of the circadian clock, we examined the cellular metabolic state in the human primary skin fibroblast model. Notably, under normal conditions, ATP levels displayed circadian oscillations, which correspond to the respective circadian pattern of mitochondrial respiration. In contrast, Aβ1–42 treatment provoked a strong dampening in the metabolic oscillations of ATP levels as well as mitochondrial respiration and in addition, induced an increased oxidized state. Overall, we gain here new insights into the deleterious cycle involved in Aβ-induced decay of the circadian rhythms leading to metabolic deficits, which may contribute to the failure in mitochondrial energy metabolism associated with the pathogenesis of AD.
Highlights
Ageing leads to a functional deterioration of many brain systems, including the circadian clock, an internal timekeeping system that generates ∼24-h rhythms in physiology and behavior
Since mitochondria were found to be a target of Aβ (Schmitt et al, 2012), leading to mitochondrial dysfunction including a decline in oxidative phosphorylation (OxPhos) and in ATP content, we investigated the impact of Aβ on ATP content and on mitochondrial oxidative metabolism with regard to rhythmic changes due to the the tight relationship between the circadian clock and metabolism (Brown, 2016; Panda, 2016)
We aimed to investigate, on the one hand, whether Aβ can directly play a role in the molecular circadian clock disturbances associated with Alzheimer’s disease (AD) and on the other hand, whether Aβ impacts the integrity of the circadian regulation of mitochondrial function, which could, in part, contribute to the AD pathogenesis
Summary
Ageing leads to a functional deterioration of many brain systems, including the circadian clock, an internal timekeeping system that generates ∼24-h rhythms in physiology and behavior. Potential molecular mechanisms include the circadian control of physiological processes such as brain metabolism, amyloid-β (Aβ) metabolism, reactive oxygen species (ROS) homeostasis, hormone secretion, autophagy, and stem cell proliferation (Hastings et al, 2007; Kang et al, 2009; Lai et al, 2012; Eckel-Mahan and Sassone-Corsi, 2013). It remains mostly unclear if or how Aβ might lead to disruption of the circadian clock which, in turn, could exacerbate the neurodegenerative processes. As the underlying mechanisms of AD onset are still unknown, it is worth considering the core clock as a potential therapeutic target for the prevention of neurodegeneration
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