Discovery of novel mechanisms by which sleep modulates Aß toxicity

Project: Research project

Project Details

Description

There is a bidirectional relationship between Alzheimer’s disease (AD) and impaired sleep, where sleep disruption often precedes the onset of cognitive dysfunction. Sleep loss and sleep fragmentation increase amyloid beta (Aβ) levels yet the molecular mechanisms by which sleep disruption impacts Aβ levels and ultimately AD pathology are poorly understood. We find that induced Aβ expression in Drosophila (a well-established model that recapitulates most AD phenotypes) disrupts sleep architecture as well as sleep-wake rhythms and that sleep disruption can, in turn, up-regulate Aβ levels and increase its toxic effects on behavior. However, the molecular mechanisms where sleep and AD intersect remain unknown.

Here we will leverage the power of high throughput genetic screening in Drosophila to identify genes that mediate enhancement of Aβ toxicity by sleep deprivation.
To identify potential mediators of sleep and circadian effects, we have profiled sleep dependent gene expression using RNA-sequencing and identified several hundred genes that are up- or down-regulated after sleep deprivation. We will apply high throughput genetic screens to test the role of these genes in mediating sleep deprivation effects on Aβ levels and/or toxicity. Specifically, our aims are:

Aim 1. To identify molecular pathways that mediate the effects of sleep deprivation on Aβ toxicity
Aim 2. To test the hypothesis that modifiers of sleep deprivation induced Aβ toxicity act via changes in Aβ levels, synapses, and/or cell death
We will focus on the discovery of novel amplifying and protective factors related to Aβ driven neurodegeneration, rather than focusing on a specific mechanism. We leverage our discovery of a bidirectional relationship between sleep/circadian rhythms and age-dependent Aβ toxicity, providing potentially novel therapeutic pathways for Alzheimer’s disease. To discover these pathways, we have developed a high throughput behavioral platform in Drosophila, a well-established AD model organism that enables in vivo screening of genetic modifiers of Aβ effects. The proposed screen integrates potential AD-relevant gene x environment interactions by identifying genes whose function may only be evident under conditions of sleep disruption. This kind of high throughput screen is not feasible in rodent models. While our initial screening is behavioral, we employ comprehensive secondary testing assessing cell death and synaptic integrity to elucidate cellular and molecular readouts of Aβ modifiers.
Our Drosophila AD model recapitulates many features present in humans, including neurodegeneration, impaired memory, and the link between sleep deprivation and increased Aβ levels. In addition, the mechanistic basis of these processes, as well as sleep and circadian rhythms, is sufficiently conserved that it will be possible to translate findings here for testing in mammalian Alzheimer’s models.
StatusActive
Effective start/end date3/1/182/28/21

Funding

  • Alzheimer's Association (AARG-17-532626)

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