PgmNr D1346: Knockdown of the Sleep and Circadian Rhythm-Regulating Protein Insomniac Exacerbates Decreased Longevity in a Drosophila model of Alzheimer’s Disease.

Authors:
Thomas S. Finn; Tyler Dewitt; Sarah Deleon; Jeremy C. Lee


Institutes
University of California, Santa Cruz, Santa Cruz, CA.


Keyword: neural degeneration

Abstract:

Alzheimer’s Disease (AD) is the leading cause of dementia in the elderly population, currently affecting over 5 million Americans.  AD is characterized by an accumulation of extracellular plaques composed of Amyloid-beta (Aβ) peptides as well as accumulation of intracellular neurofibrillary tangles (NFTs).  Recently, it was reported that patients with AD who also suffer from low sleep quality, have increased Aβ deposition in the brain compared to patients with AD that experience normal sleep patterns. Experiments in mice have shown that sleep is associated with a 60% increase in the interstitial space of the brain and greatly increases the rate at which Aβ is cleared (Xie, et al., 2013). In a recent Genome Wide Association Study, the KCTD2 locus in humans was further implicated in AD (Boada, et al., 2013). Interestingly, homologs of this locus are present in many animal models, such as the insomniac locus in Drosophila. Loss-of-function mutations of insomniac result in a severe sleep deprivation and dysfunction in circadian regulation (Stavropoulos & Young, 2011; Pfeiffenberger & Allada, 2012).  

We have conducted experiments to test the effects of sleep and/or circadian dysfunction on AD-like pathology in a Drosophila model of AD.  Our central hypothesis is that inducing sleep deprivation/circadian dysfunction, as a result of knocking down Insomniac, will accelerate and increase Aβ deposition, resulting in more severe AD-like pathology.  To test this hypothesis, we are using a Drosophila AD model that expresses human Aβ42 in the CNS under an elav-Gal4 driver. These flies exhibit decreased longevity as compared to control flies; they also exhibit abnormal behavior and deposition of Aβ aggregates in the brain.  In these AD model flies, we have knocked down Insomniac levels by also expressing shRNA that targets insomniac mRNA. We find that the severity of AD-like pathology, as measured by decreases in longevity, are significantly exacerbated by knocking down Insomniac levels; i.e. the AD model flies in which Insomniac is knocked down have a shorter mean lifespan than AD model flies which express wild type levels of Insomniac.  This exacerbation of the longevity defect appears to be an interaction between the Insomniac knockdown and the effects of Aβ, and is not simply an additive effect on longevity. Control flies only expressing the Insomniac shRNA  showed no deviation in their survivorship compared to wild-type flies. We are currently conducting experiments to assess whether the knockdown of Insomniac also exacerbates other aspects of AD-like pathology in our flies, including effects on behavior, as measured by the RING assay, and on levels of Ab deposition in the brain.