Induction of ganglioside synthesis in Drosophila brain accelerates assembly of amyloid \u03b2 protein

Yasutoyo Yamasaki,Akemi Suzuki,Leo Tsuda,Katsuhiko Yanagisawa

doi:10.1038/s41598-018-26294-8

Abstract

The assembly and deposition of amyloid β protein (Aβ) is a fundamental event during the early stages of Alzheimer’s disease (AD) and cerebral amyloid angiopathy. A growing body of evidence indicates that gangliosides form a pathological platform for the generation of ganglioside-bound Aβ, which facilitates the assembly of soluble Aβs; however, the molecular mechanisms underlying the binding of Aβ to gangliosides in the brain remain unclear due to the lack of an in vivo system that may address this issue. In insects, including the fruit fly Drosophila melanogaster, gangliosides are not intrinsically present at a detectable level. We herein demonstrate that ganglioside expression is inducible in Drosophila via the expression of transgenes of ganglioside synthesis enzymes and the feeding of exogenous sialic acid, and also that the induction of ganglioside synthesis significantly accelerates Aβ assembly in vivo. Our results support the hypothesis that gangliosides are responsible for Aβ assembly in vivo and also provide an opportunity to develop a valuable model for basic research as well as a therapeutic strategy for AD.

Highlights

Gangliosides are glycosphingolipids containing one or more sialic acid (SA) residues and are evolutionarily conserved among mammals
The Dutch-type (E22Q) mutation causes amyloid deposition predominantly in the cerebral vessel wall[5,6], suggesting that this wall, which is mainly composed of vascular smooth muscle cells, expresses unique gangliosides that favorably initiate the assembly of Dutch-type amyloid β protein (Aβ)
In the initial step in the mammalian ganglioside synthesis pathway, GM3 is generated from glucosylceramide (GlcCer) via lactosylceramide (LacCer) (Fig. 1)

Summary

Introduction

Gangliosides are glycosphingolipids containing one or more sialic acid (SA) residues and are evolutionarily conserved among mammals. The molecular characterization of this Aβ species, named ganglioside-bound Aβ (GAβ), prompted us to hypothesize that Aβ binds to GM1 on neuronal membranes, leading to the adoption of an altered conformation that is distinct from those of soluble and fibril Aβs, and that this altered conformation subsequently facilitates the assembly of soluble Aβs into fibrils by acting as a seed[3,4]. The Dutch-type (E22Q) mutation causes amyloid deposition predominantly in the cerebral vessel wall[5,6], suggesting that this wall, which is mainly composed of vascular smooth muscle cells, expresses unique gangliosides that favorably initiate the assembly of Dutch-type Aβ. In order to examine this possibility, we analyzed ganglioside species in vascular smooth muscle cells and found the exclusive expression of GM3 and, to a lesser extent, GM27. We demonstrated that Dutch-type Aβ assembly was significantly accelerated in GM3-induced flies

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