title: Aberrant Axonal Arborization of PDF Neurons Induced by Aβ42-Mediated JNK Activation Underlies Sleep Disturbance in an Alzheimer's Model.
abstract: Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila Aβ42 AD model, we show that Aβ42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in Aβ42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in Aβ42 flies. Finally, inhibition of JNK activation in Aβ42 flies restores nighttime sleep loss, decreases Aβ42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by Aβ42 burden, a key initiator of a complex pathogenic cascade in AD.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China.|Shanghai Key Laboratory of Psychotic Disorders (No.13dz2260500), Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Song
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Feng
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China.|School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China.|School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Chen
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China.|School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.|Institute of Systems Biomedicine, Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
authors.forename: Zhaohuan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, China. yoping@sjtu.edu.cn.|Shanghai Key Laboratory of Psychotic Disorders (No.13dz2260500), Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China. yoping@sjtu.edu.cn.
authors.forename: Yong
authors.identifier: http://orcid.org/0000-0003-1066-5471
authors.initials: Y
authors.lastname: Ping
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D020935:MAP Kinase Signaling System / Q000235:genetics*; D009043:Motor Activity / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D020447:Parasomnias / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Axonal growth; Drosophila; JNK; Sleep