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

Lüchtenborg AM, Katanaev VL - Mol Brain (2014)

Bottom Line: 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.We found that the action of Aβ42 specifically in the glutamatergic motoneurons is responsible for the reduced survival.Our 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, Lausanne, 1005, Switzerland. anne-marie.luchtenborg@unil.ch.

ABSTRACT

Background: Alzheimer'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.

Findings: Expression 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.

Conclusions: Our 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.

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Related in: MedlinePlus

Expression of Aβ42 in the nervous system dramatically reduces the life span. (A-B) Survival curves of the indicated genotypes expressed either with the pan-neuronal driver elav-Gal4(A) or the driver D42-Gal4 which expresses in the glutamatergic motoneurons (B). P < 0.0001 comparing the controls elav-Gal4 and D42-Gal4 to Aβ42 expression, respectively. p = 0.0028 comparing Aβ42; D42-Gal4 and Aβ42/OK371-Gal4; D42-Gal4. Co-expression of Fz2 or RNAi-Sgg did not rescue life span. P-values are calculated with the Log-rank test.
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Fig1: Expression of Aβ42 in the nervous system dramatically reduces the life span. (A-B) Survival curves of the indicated genotypes expressed either with the pan-neuronal driver elav-Gal4(A) or the driver D42-Gal4 which expresses in the glutamatergic motoneurons (B). P < 0.0001 comparing the controls elav-Gal4 and D42-Gal4 to Aβ42 expression, respectively. p = 0.0028 comparing Aβ42; D42-Gal4 and Aβ42/OK371-Gal4; D42-Gal4. Co-expression of Fz2 or RNAi-Sgg did not rescue life span. P-values are calculated with the Log-rank test.

Mentions: Pan-neuronal expression of secreted Aβ42 (using the elav-Gal4 driver) has previously been shown to reduce the life span of Drosophila [15,16]. We recapitulated these findings (Figure 1A) and further showed that a similar reduction in the life span can be achieved through Aβ42 expression by a motoneuron-specific driver D42-Gal4 (Figure 1B). Indeed, Aβ42 caused a reduction of the median survival from 30 days (elav-Gal4 control, n = 62) to 10 days (elav-Gal4; UAS-Aβ42, n = 74) (p < 0.0001, Log-rank test) and of the maximal life span from 42 to 16 days when the pan-neuronal driver was used (Figure 1A), and from 35 days (D42-Gal4 control, n = 60) to 12 days (D42-Gal4; UAS-Aβ42, n = 59) (p < 0.0001, Log-rank test) and the maximal life span from 49 to 19 days when the motoneuron-specific driver was used (Figure 1B). This effect is dose-dependent: increasing the amount of Gal4 produced per cell by adding another motoneuron-specific driver OK371-Gal4 to D42-Gal4 to express the Aβ42 peptide further reduced the median life span to 10 days (p = 0.0028, Log-rank test) and the maximal survival to 14 days (Figure 1B). Cumulatively, these findings suggest that the major effect of Aβ42 on the life span observed previously [15,16] by the pan-neuronal Aβ42 expression takes place in glutamatergic neurons.Figure 1


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

Lüchtenborg AM, Katanaev VL - Mol Brain (2014)

Expression of Aβ42 in the nervous system dramatically reduces the life span. (A-B) Survival curves of the indicated genotypes expressed either with the pan-neuronal driver elav-Gal4(A) or the driver D42-Gal4 which expresses in the glutamatergic motoneurons (B). P < 0.0001 comparing the controls elav-Gal4 and D42-Gal4 to Aβ42 expression, respectively. p = 0.0028 comparing Aβ42; D42-Gal4 and Aβ42/OK371-Gal4; D42-Gal4. Co-expression of Fz2 or RNAi-Sgg did not rescue life span. P-values are calculated with the Log-rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4232725&req=5

Fig1: Expression of Aβ42 in the nervous system dramatically reduces the life span. (A-B) Survival curves of the indicated genotypes expressed either with the pan-neuronal driver elav-Gal4(A) or the driver D42-Gal4 which expresses in the glutamatergic motoneurons (B). P < 0.0001 comparing the controls elav-Gal4 and D42-Gal4 to Aβ42 expression, respectively. p = 0.0028 comparing Aβ42; D42-Gal4 and Aβ42/OK371-Gal4; D42-Gal4. Co-expression of Fz2 or RNAi-Sgg did not rescue life span. P-values are calculated with the Log-rank test.
Mentions: Pan-neuronal expression of secreted Aβ42 (using the elav-Gal4 driver) has previously been shown to reduce the life span of Drosophila [15,16]. We recapitulated these findings (Figure 1A) and further showed that a similar reduction in the life span can be achieved through Aβ42 expression by a motoneuron-specific driver D42-Gal4 (Figure 1B). Indeed, Aβ42 caused a reduction of the median survival from 30 days (elav-Gal4 control, n = 62) to 10 days (elav-Gal4; UAS-Aβ42, n = 74) (p < 0.0001, Log-rank test) and of the maximal life span from 42 to 16 days when the pan-neuronal driver was used (Figure 1A), and from 35 days (D42-Gal4 control, n = 60) to 12 days (D42-Gal4; UAS-Aβ42, n = 59) (p < 0.0001, Log-rank test) and the maximal life span from 49 to 19 days when the motoneuron-specific driver was used (Figure 1B). This effect is dose-dependent: increasing the amount of Gal4 produced per cell by adding another motoneuron-specific driver OK371-Gal4 to D42-Gal4 to express the Aβ42 peptide further reduced the median life span to 10 days (p = 0.0028, Log-rank test) and the maximal survival to 14 days (Figure 1B). Cumulatively, these findings suggest that the major effect of Aβ42 on the life span observed previously [15,16] by the pan-neuronal Aβ42 expression takes place in glutamatergic neurons.Figure 1

Bottom Line: 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.We found that the action of Aβ42 specifically in the glutamatergic motoneurons is responsible for the reduced survival.Our 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, Lausanne, 1005, Switzerland. anne-marie.luchtenborg@unil.ch.

ABSTRACT

Background: Alzheimer'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.

Findings: Expression 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.

Conclusions: Our 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.

Show MeSH
Related in: MedlinePlus