title: Sleep interacts with aβ to modulate intrinsic neuronal excitability.
abstract: BACKGROUND
  Emerging data suggest an important relationship between sleep and Alzheimer's disease (AD), but how poor sleep promotes the development of AD remains unclear.
  
  
  RESULTS
  Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. β-amyloid (Aβ) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases Aβ burden. Moreover, enhancing sleep reduces Aβ deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on Aβ, and decreasing neuronal activity blocks the elevated Aβ accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as Aβ expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates Aβ-induced hyperexcitability and suggest that defects in specific K(+) currents underlie the hyperexcitability caused by sleep loss and Aβ expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to Aβ-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan.
  
  
  CONCLUSIONS
  Our findings directly link sleep loss to changes in neuronal excitability and Aβ accumulation and further suggest that neuronal hyperexcitability is an important mediator of Aβ toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of Aβ, a key pathogenic step in the development of AD.
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tabuchi
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Shahnaz R
authors.initials: SR
authors.lastname: Lone
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Qili
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Spira
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: marknwu@jhmi.edu.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Wu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D000927:Anticonvulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D006801:Humans; D000077287:Levetiracetam; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D012890:Sleep / Q000235:genetics / Q000502:physiology*; D012892:Sleep Deprivation / Q000235:genetics / Q000503:physiopathology
chemical_list: D016229:Amyloid beta-Peptides; D000927:Anticonvulsants; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D000077287:Levetiracetam; D010889:Piracetam