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

• Published in: PLoS ONE
• Main Authors: Long, Dani M., Blake, Matthew R., Dutta, Sudeshna, Holbrook, Scott D., Kotwica-Rolinska, Joanna, Kretzschmar, Doris, Giebultowicz, Jadwiga M.
• Format: Text
• Language: English
• Published: Public Library of Science 2014
• Subjects: Research Article; Arctic
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149435; http://www.ncbi.nlm.nih.gov/pubmed/25171136; https://doi.org/10.1371/journal.pone.0106068

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.