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Neurobiol Sleep Circadian Rhythms. 2017 Jan;2:15-26. doi: 10.1016/j.nbscr.2016.09.001. Epub 2016 Sep 28.

Enhanced sleep reverses memory deficits and underlying pathology in Drosophila models of Alzheimer's disease.

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Department of Neuroscience, Washington University in St. Louis, 660 S. Euclid Ave, St. Louis, Missouri, U.S.A.
Department of Neurobiology, University of California: Los Angeles Los Angeles, California, U.S.A.
Surrey Sleep Research Centre, Faculty of Health and Medical Sciences University of Surrey Guildford Surrey, GU2 7XH, United Kingdom.
Queensland Brain Institute, The University of Queensland, Brisbane Qld 4072 Australia.


To test the hypothesis that sleep can reverse cognitive impairment during Alzheimer's disease, we enhanced sleep in flies either co-expressing human amyloid precursor protein and Beta-secretase (APP:BACE), or in flies expressing human tau. The ubiquitous expression of APP:BACE or human tau disrupted sleep. The sleep deficits could be reversed and sleep could be enhanced when flies were administered the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Expressing APP:BACE disrupted both Short-term memory (STM) and Long-term memory (LTM) as assessed using Aversive Phototaxic Suppression (APS) and courtship conditioning. Flies expressing APP:BACE also showed reduced levels of the synaptic protein discs large (DLG). Enhancing sleep in memory-impaired APP:BACE flies fully restored both STM and LTM and restored DLG levels. Sleep also restored STM to flies expressing human tau. Using live-brain imaging of individual clock neurons expressing both tau and the cAMP sensor Epac1-camps, we found that tau disrupted cAMP signaling. Importantly, enhancing sleep in flies expressing human tau restored proper cAMP signaling. Thus, we demonstrate that sleep can be used as a therapeutic to reverse deficits that accrue during the expression of toxic peptides associated with Alzheimer's disease.

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