Abstract
Circadian clocks coordinate physiological, neurological, and behavioral functions into circa 24 hour rhythms, and the molecular mechanisms underlying circadian clock oscillations are conserved from Drosophila to humans. Clock oscillations and clock-controlled rhythms are known to dampen during aging; additionally, genetic or environmental clock disruption leads to accelerated aging and increased susceptibility to age-related pathologies. Neurodegenerative diseases, such as Alzheimer's disease (AD), are associated with a decay of circadian rhythms, but it is not clear whether circadian disruption accelerates neuronal and motor decline associated with these diseases. To address this question, we utilized transgenic Drosophila expressing various Amyloid-β (Aβ) peptides, which are prone to form aggregates characteristic of AD pathology in humans. We compared development of AD-like symptoms in adult flies expressing Aβ peptides in the wild type background and in flies with clocks disrupted via a null mutation in the clock gene period (per01). No significant differences were observed in longevity, climbing ability and brain neurodegeneration levels between control and clock-deficient flies, suggesting that loss of clock function does not exacerbate pathogenicity caused by human-derived Aβ peptides in flies. However, AD-like pathologies affected the circadian system in aging flies. We report that rest/activity rhythms were impaired in an age-dependent manner. Flies expressing the highly pathogenic arctic Aβ peptide showed a dramatic degradation of these rhythms in tune with their reduced longevity and impaired climbing ability. At the same time, the central pacemaker remained intact in these flies providing evidence that expression of Aβ peptides causes rhythm degradation downstream from the central clock mechanism.
Highlights
The circadian clock coordinates daily physiological, neurological, and behavioral rhythms which maintain temporal homeostasis
We investigated Alzheimer’s disease (AD) model flies with a normal or disrupted circadian system to address three main questions: 1) Does arrhythmicity caused by the loss of the core clock gene period accelerate AD-like phenotypes in the fly model? 2) Does AD progression alter circadian locomotor activity rhythms in flies? 3) Is the central pacemaker functional in aging AD-model flies? In order to address these questions, we used transgenic Drosophila expressing human Ab40, Ab42, or Ab42arc fragments [15] under the control of the pan-neuronal driver elav-GAL4 in clockcompetent or clock-disrupted per01 backgrounds
Lifespan reduction caused by Ab peptides is not exacerbated by the by loss of the clock gene period To determine whether disruption of the clock affects longevity in AD model flies, we compared the lifespan of flies expressing various Ab peptides in wild type and clock-disrupted mutant backgrounds
Summary
The circadian clock coordinates daily physiological, neurological, and behavioral rhythms which maintain temporal homeostasis. The positive arm proteins in Drosophila are CLOCK (CLK) and CYCLE (CYC) which form a dimer driving the transcription of the period (per) and timeless (tim) genes, which encode the negative arm clock proteins. Flies with null mutations in any one of these core clock genes have abolished clock function and are behaviorally arrhythmic [1]. Mice lacking the clock protein BMAL1 (homolog of fly CYC protein) show several symptoms of aging [2,3], and loss of BMAL1 in the brain may lead to neurodegeneration [4]. A null mutation in the clock gene per leads to higher accumulation of ROS, protein carbonyls, and peroxidated lipids during aging [5,6], suggesting that antioxidant defenses are compromised by the loss of clock function. We reported recently that disruptions in clock function in flies accelerated aging in neurodegeneration-prone sniffer and swiss cheese mutants [6]
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