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