Laboratory of Animal Models of Aging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Morioka 7-430, Obu, Aichi, 474-8511, Japan.
Institute of Glycoscience, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa, 259-1292, Japan.
Sci Rep. 2018 May 29;8(1):8345. doi: 10.1038/s41598-018-26294-8.
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.
淀粉样蛋白 β （Aβ）的组装和沉积是阿尔茨海默病（AD）和脑淀粉样血管病早期的基本事件。越来越多的证据表明，神经节苷脂形成了神经节苷脂结合 Aβ 的病理平台，从而促进了可溶性 Aβ 的组装；然而，由于缺乏可能解决这一问题的体内系统，Aβ与脑中神经节苷脂结合的分子机制仍不清楚。在昆虫中，包括黑腹果蝇 Drosophila melanogaster，神经节苷脂的含量在可检测水平上不存在。我们在此证明，通过表达神经节苷脂合成酶的转基因和喂食外源唾液酸，可诱导果蝇中神经节苷脂的表达，并且神经节苷脂的合成诱导可显著加速体内 Aβ的组装。我们的结果支持了这样一种假设，即神经节苷脂是体内 Aβ组装的原因，并为基础研究提供了一个有价值的模型，也为 AD 提供了一种治疗策略。
