Dopamine, sleep, and neuronal excitability modulate amyloid-ß-mediated forgetting in Drosophila.

Alzheimer disease (AD) is one of the main causes of age-related dementia and neurodegeneration. However, the onset of the disease and the mechanisms causing cognitive defects are not well understood. Aggregation of amyloidogenic peptides is a pathological hallmark of AD and is assumed to be a central component of the molecular disease pathways. Pan-neuronal expression of Aß42Arctic peptides in Drosophila melanogaster results in learning and memory defects. Surprisingly, targeted expression to the mushroom bodies, a center for olfactory memories in the fly brain, does not interfere with learning but accelerates forgetting. We show here that reducing neuronal excitability either by feeding Levetiracetam or silencing of neurons in the involved circuitry ameliorates the phenotype. Furthermore, inhibition of the Rac-regulated forgetting pathway could rescue the Aß42Arctic-mediated accelerated forgetting phenotype. Similar effects are achieved by increasing sleep, a critical regulator of neuronal homeostasis. Our results provide a functional framework connecting forgetting signaling and sleep, which are critical for regulating neuronal excitability and homeostasis and are therefore a promising mechanism to modulate forgetting caused by toxic Aß peptides.

Sleep interacts with aß 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. 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.