TY - JOUR
T1 - Sleep interacts with aβ to modulate intrinsic neuronal excitability
AU - Tabuchi, Masashi
AU - Lone, Shahnaz R.
AU - Liu, Sha
AU - Liu, Qili
AU - Zhang, Julia
AU - Spira, Adam P.
AU - Wu, Mark N.
N1 - Funding Information:
We thank Drs. Tzumin Lee, Damian Crowther, Mark Stopfer, and Paul Shaw and the Bloomington Stock Center for fly stocks. We thank members of the M.N.W. laboratory, Tom Lloyd, and Marilyn Albert for helpful feedback. This work was funded by NINDS R01NS079584 (M.N.W.), a Burroughs-Wellcome Fund Career Award for Medical Scientists (M.N.W.), an Alzheimer’s Association New Investigator Research Grant (M.N.W.), and a Synaptic Plasticity and Cognitive Disorders Award from the Brain Science Institute at Johns Hopkins (A.P.S. and M.N.W.).
Publisher Copyright:
© 2015 Elsevier Ltd All rights reserved.
PY - 2015/3/16
Y1 - 2015/3/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cub.2015.01.016
DO - 10.1016/j.cub.2015.01.016
M3 - Article
C2 - 25754641
AN - SCOPUS:84926297916
SN - 0960-9822
VL - 25
SP - 702
EP - 712
JO - Current Biology
JF - Current Biology
IS - 6
ER -