Lack of evidence of the interaction of the Aβ peptide with the Wnt signaling cascade in Drosophila models of Alzheimer's disease

Abstract

BackgroundAlzheimer’s disease (AD) is the leading form of dementia worldwide. The Aβ-peptide is believed to be the major pathogenic compound of the disease. Since several years it is hypothesized that Aβ impacts the Wnt signaling cascade and therefore activation of this signaling pathway is proposed to rescue the neurotoxic effect of Aβ.FindingsExpression of the human Aβ42 in the Drosophila nervous system leads to a drastically shortened life span. We found that the action of Aβ42 specifically in the glutamatergic motoneurons is responsible for the reduced survival. However, we find that the morphology of the glutamatergic larval neuromuscular junctions, which are widely used as the model for mammalian central nervous system synapses, is not affected by Aβ42 expression. We furthermore demonstrate that genetic activation of the Wnt signal transduction pathway in the nervous system is not able to rescue the shortened life span or a rough eye phenotype in Drosophila.ConclusionsOur data confirm that the life span is a useful readout of Aβ42 induced neurotoxicity in Drosophila; the neuromuscular junction seems however not to be an appropriate model to study AD in flies. Additionally, our results challenge the hypothesis that Wnt signaling might be implicated in Aβ42 toxicity and might serve as a drug target against AD.

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

“…Consistently, GSK3-β inhibition can restore some of the Aβ toxic effects, similar to lithium or Congo-Red treatments (Crowther et al, 2004;Sofola-Adesakin et al, 2014;Sofola et al, 2010). By contrast, other reports found no restoration when GSK3-β was down-regulated in Aβ expressing neurons, claiming no Wnt-Aβ interaction in Drosophila AD models (Lüchtenborg and Katanaev, 2014). PI3K inhibition by downregulation of p65 regulatory subunit has also been used in Aβ, showing prevention of Aβ-induced neuronal electrophysiological defects (Chiang et al, 2010).…”

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposit formation

“…Consistently, GSK3-β inhibition can restore some of the Aβ toxic effects, similar to lithium or Congo red treatments (Crowther et al, 2004;Sofola et al, 2010;Sofola-Adesakin et al, 2014). By contrast, other reports found no restoration when GSK3-β was down-regulated in Aβ-expressing neurons, claiming no Wnt-Aβ interaction in Drosophila AD models (Lüchtenborg and Katanaev, 2014). PI3K inhibition by down-regulation of the p65 regulatory subunit has also been used in Aβ experiments, showing prevention of Aβ-induced neuronal electrophysiological defects (Chiang et al, 2010).…”

Humanization ofDrosophilaGαo to modelGNAO1paediatric encephalopathies

“…The following primary antibodies were used: mouse monoclonal antibody against bovine Gαo (1:20 dilution, Santa Cruz Biotechnology, sc-13532) and rabbit anti-dGao (1:50; (Luchtenborg et al, 2014)).…”

“…Animal models have the instrumental role in deciphering the disease mechanisms and in identifying / validating the treatment routes. Drosophila has been used to model a variety of human maladies, especially neurological ones (Bellen et al, 2019;Bolus et al, 2020;Katanaev et al, 2020;Katanaev and Kryuchkov, 2011;Luchtenborg and Katanaev, 2014). As the first step towards modelling GNAO1 paediatric encephalopathies in the fruit fly, we here describe humanization of the Drosophila Gαo locus, finding the human protein fully replaces the insect one's functions without any aberrations.…”

“…Driven by the pivotal roles of Gαo and by the fact that the list of its molecular targets was remarkably short (Jiang and Bajpayee, 2009) Kopein and Katanaev, 2009;Lin and Katanaev, 2013;Lin et al, 2014;Luchtenborg et al, 2014;Purvanov et al, 2010 Of the point mutations identified within the coding region of GNAO1 in paediatric encephalopathy patients, all correspond to highly conserved residues ( Fig. 1A), indicating their involvement in basic Gαo functions.…”