2022-08-12 ペンシルベニア州立大学(PennState)
研究チームは、細胞膜に存在する分子であるモノシアロテトラヘキソシルガングリオシド(GM1)が、アミロイドβ(Aβ)というタンパク質からなる有害なオリゴマー、すなわち有害タンパク質クラスター形成に寄与することを明らかにした。このタンパク質の凝集は、アルツハイマー病の発症と進行に関連している。
細胞膜組成、特にGM1は、これらのタンパク質クラスターの形成に関与していることが知られており、Aβ線維の形成を促進するだけでなく、Aβオリゴマーの膜上での維持も促進することがわかった。
<関連情報>
- https://www.psu.edu/news/research/story/neuron-membrane-lipid-may-contribute-alzheimers-development-progression/
- https://pubs.acs.org/doi/10.1021/acschemneuro.2c00221
モノシアロテトラヘキソシルガングリオシドは、初期のAβ42オリゴマーの形成と維持を促進する Monosialotetrahexosylganglioside Promotes Early Aβ42 Oligomer Formation and Maintenance
Dong Yan Zhang, Jian Wang, Rebecca M. Fleeman, Madison K. Kuhn, Matthew T. Swulius, Elizabeth A. Proctor, and Nikolay V. Dokholyan
ACS Chemical Neuroscience Published:June 17, 2022
DOI:https://doi.org/10.1021/acschemneuro.2c00221
Abstract
The aggregation of the amyloid beta (Aβ) peptide is associated with Alzheimer’s disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of Aβ fibrils, yet little is known about the roles of GM1 in the early steps of Aβ oligomer formation. Here, by using GM1-contained liposomes as a mimic of the neuronal cell membrane, we demonstrate that GM1 is a critical trigger of Aβ oligomerization and aggregation. We find that GM1 not only promotes the formation of Aβ fibrils but also facilitates the maintenance of Aβ42 oligomers on liposome membranes. We structurally characterize the Aβ42 oligomers formed on the membrane and find that GM1 captures Aβ by binding to its arginine-5 residue. To interrogate the mechanism of Aβ42 oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the Aβ42 ion channel hypothesis. Finally, we determine the toxicity of Aβ42 oligomers formed on membranes. Overall, by uncovering the roles of GM1 in mediating early Aβ oligomer formation and maintenance, our work provides a novel direction for pharmaceutical research for AD.
