Relationships between the Circadian System and Alzheimer's Disease-Like Symptoms in Drosophila

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.

Manipulations of amyloid precursor protein cleavage disrupt the circadian clock in aging Drosophila

“…While we report here that the loss of behavioral rhythms after manipulation of dBACE is associated with reduced expression of clock genes in the central pacemaker, recent work showed that expression of human Aβ peptides leads to disruption of rest activity rhythms without interfering with PER oscillations in the central pacemaker (Chen et al, 2014; Long et al, 2014). Even strongly neurotoxic Aβ peptides, such as Aβ 42 arctic, did not cause rhythm disruption when expressed in central pacemaker neurons; rather, pan-neuronal expression was required (Chen et al, 2014; Long et al, 2014).…”

“…Even strongly neurotoxic Aβ peptides, such as Aβ 42 arctic, did not cause rhythm disruption when expressed in central pacemaker neurons; rather, pan-neuronal expression was required (Chen et al, 2014; Long et al, 2014). The fact that even the most neurotoxic Aβ peptides are not capable of dampening PER oscillation in pacemaker neurons suggests that Aβ production does not affect clock oscillations and that it is not Aβ production that causes the phenotype we observe upon over-expression of dBACE.…”

“…Recent reports showed that pathogenic human amyloid peptides disrupt behavioral rest-activity rhythms in Drosophila but are not sufficient to disrupt molecular oscillations of PERIOD (PER) in central pacemaker neurons (Chen et al, 2014; Long et al, 2014). Here, we manipulated AD-related genes in the fruit fly, Drosophila melanogaster in order to understand endogenous pathways that may interfere with the circadian system.…”

Aging and circadian rhythms

“…When human amyloid β (Aβ) peptides were expressed in flies to create Alzheimer disease (AD) models, disruption of a functional circadian system via per -null mutation had little effect on fly lifespan or healthspan [20]. On the other hand, overexpression of pathogenic Aβ42 peptide carrying the arctic mutation (Aβ42arc) led to accelerated decline in rest/activity rhythms, combined with loss of vertical climbing ability and increased neurodegeneration even in 15–20 days old flies [20,21]. Surprisingly, central clock neurons of these flies were intact and exhibited robust cycling in PER with a peak and trough that was not significantly different from age matched controls [20,21].…”

“…On the other hand, overexpression of pathogenic Aβ42 peptide carrying the arctic mutation (Aβ42arc) led to accelerated decline in rest/activity rhythms, combined with loss of vertical climbing ability and increased neurodegeneration even in 15–20 days old flies [20,21]. Surprisingly, central clock neurons of these flies were intact and exhibited robust cycling in PER with a peak and trough that was not significantly different from age matched controls [20,21]. These studies suggest that damage to clock output pathways downstream of the central clock could be responsible for the loss of rest/activity rhythms in AD model flies.…”