title: 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.
authors.affiliation: Department of Integrative Biology, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Blake
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Holbrook
authors.affiliation: Department of Integrative Biology, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kotwica-Rolinska
authors.affiliation: Department of Integrative Biology, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Chow
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Doris
authors.initials: D
authors.lastname: Kretzschmar
authors.affiliation: Department of Integrative Biology, Oregon State University, Corvallis, OR 97331, USA. Electronic address: giebultj@science.oregonstate.edu.
authors.forename: Jadwiga M
authors.initials: JM
authors.lastname: Giebultowicz
mesh_terms: D000367:Age Factors; D000375:Aging; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002490:Central Nervous System / Q000166:cytology; D057906:Circadian Clocks / Q000235:genetics*; D019483:Disintegrins / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D005583:Fourier Analysis; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008136:Longevity; D008666:Metalloendopeptidases / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D056950:Period Circadian Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D019483:Disintegrins; D029721:Drosophila Proteins; D056950:Period Circadian Proteins; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; C100953:KUZ protein, Drosophila; D008666:Metalloendopeptidases
keywords: Alzheimer's disease; Amyloid intracellular domain; Amyloid precursor protein; BACE; Circadian rhythms; Drosophila; period gene