Sleep Interacts with Aβ to Modulate Intrinsic Neuronal Excitability

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. beta-amyloid (A beta) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases A beta burden. Moreover, enhancing sleep reduces A beta deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on A beta, and decreasing neuronal activity blocks the elevated A beta accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as A beta expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates A beta-induced hyperexcitability and suggest that defects in specific K+ currents underlie the hyperexcitability caused by sleep loss and A beta expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to A beta-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan. Conclusions: Our findings directly link sleep loss to changes in neuronal excitability and A beta accumulation and further suggest that neuronal hyperexcitability is an important mediator of A beta toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of A beta, a key pathogenic step in the development of AD.