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

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe cognitive deterioration. While causes of AD pathology are debated, a large body of evidence suggests that increased cleavage of Amyloid Precursor Protein (APP) producing the neurotoxic Amyloid-β (Aβ) peptide plays a fundamental role in AD pathogenesis. One of the detrimental behavioral symptoms commonly associated with AD is the fragmentation of sleep-activity cycles with increased nighttime activity and daytime naps in humans. Sleep-activity cycles, as well as physiological and cellular rhythms, which may be important for neuronal homeostasis, are generated by a molecular system known as the circadian clock. Links between AD and the circadian system are increasingly evident but not well understood. Here we examined whether genetic manipulations of APP-like (APPL) protein cleavage in Drosophila melanogaster affect rest-activity rhythms and core circadian clock function in this model organism. We show that the increased β-cleavage of endogenous APPL by the β-secretase (dBACE) severely disrupts circadian behavior and leads to reduced expression of clock protein PER in central clock neurons of aging flies. Our data suggest that behavioral rhythm disruption is not a product of APPL-derived Aβ production but rather may be caused by a mechanism common to both α and β-cleavage pathways. Specifically, we show that increased production of the endogenous Drosophila Amyloid Intracellular Domain (dAICD) caused disruption of circadian rest-activity rhythms, while flies overexpressing endogenous APPL maintained stronger circadian rhythms during aging. In summary, our study offers a novel entry point toward understanding the mechanism of circadian rhythm disruption in Alzheimer’s disease.

Alzheimer's Disease and Sleep–Wake Disturbances: Amyloid, Astrocytes, and Animal Models

“…However, ANLS uncoupling may also allow glutamate spillover, which would facilitate and increase surrounding synaptic excitability, excitotoxicity, and neurodegeneration. This final step is supported by findings that A␤ can induce glutamate release from astrocytes, leading to synapse loss (Talantova et al, 2013), and that A␤ alters metabolic functions of astrocytes (Allaman et al, 2010). These events promote further wakefulnessinduced A␤ release, aggregation, and ANLS uncoupling, establishing a vicious cycle underlying AD pathology.…”

“…How might astrocytes and sleep-related ANLS mechanisms be tied to A␤ clearance in AD pathophysiology? In mice, astrocytic expression of the proteins low-density lipoprotein receptor (Basak et al, 2012) and ApoE (Verghese et al, 2013) regulate the uptake and degradation of A␤ species, whereas astrocyte dysfunction promotes A␤ aggregation. For example, disrupting normal astrocyte activation via deletion of glial fibrillary acidic protein and Vimetin enhances A␤ aggregation, whereas enhancing astrocytic autophagic processing via transcriptional factor EB overexpression mitigates amyloid plaque pathology in mice (Kraft et al, 2013;Xiao et al, 2014).…”

APP deficiency results in resistance to obesity but impairs glucose tolerance upon high fat feeding

“…Some insight may be gained from studies on circadian rhythm in AD models that demonstrate disruption of circadian rhythmicity with increased Aβ deposition, but do not provide further insight into the metabolic outcomes (Sterniczuk et al 2010). Data obtained from Drosophila melanogaster suggest that fragmentation of behavioural rhythmicity is attributable to both α-and β-processing of APP (Blake et al 2015), which may further highlight the differences observed in energy balance and activity between the previously published BACE1-deficient mice vs APP KO mice from this study. These studies highlight the complexity in APP-mediated regulation of whole body energy homeostasis and as we have recently hypothesised, could indicate that peptides derived from the amyloidogenic and non-amyloidogenic processing of APP could have different effects on aspects of systemic metabolism (Czeczor & McGee 2017).…”

Aging and the clock: Perspective from flies to humans

“…The cost‐effectiveness, genetic tractability, high throughput assays and availability of tools to manipulate neuronal properties with spatiotemporal accuracy of Drosophila have propelled it to the forefront as a competitive model for rapid identification of the cellular and molecular mechanisms underlying aging‐related diseases including neurodegenerative diseases (Blake et al., ; Gerstner et al., ; Krishnan, Kretzschmar, Rakshit, Chow & Giebultowicz, ); cardiovascular diseases (Piazza & Wessells, ; Yu, Daniels, Glaser & Wolf, ; Zarndt et al., ), cancer (Christofi & Apidianakis, ; Rudrapatna, Cagan & Das, ); diabetes and obesity (Alfa & Kim, ; Park et al., ; Trinh & Boulianne, ). As a model, Drosophila has also been used for evaluating the efficacy of potential therapeutic drugs to treat aging‐related diseases and disorders (Das & Cagan, ; Palandri et al., ).…”