Lipid transport across the blood-brain barrier

• Applicant: Dr. Lars Kuerschner
• Subject Area: Biochemistry ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 404540666

• Final Report Year: 2023

Final Report Abstract

In this project the lipid transport across the blood-brain barrier (BBB) was investigated. For this purpose, the alkyne lipid tracer technology, which has opened up a new era in lipid biology and metabolism research, was used. These non-radioactive tracers are fully compatible with modern analytical methods and therefore allow correlative tracking of lipid localization and metabolism at the highest spatial and analytical resolution. Initially, the project developed methods to analytically track alkyne lipids labelled on their head group using super-resolution microscopy and quantitative mass spectrometry (MS). The simultaneous analysis of several MS samples (multiplexing) was successfully established. Also a protocol for the parallel MS tracking of several lipid tracers (parallel multi-labeling) was developed. The new methods were then used to study in vitro models of BBB. The individual contributions of the main cell types of BBB, capillary endothelial cells and astrocytes, were investigated in detail by characterizing their activities in lipid uptake, metabolism and transport. It was possible to collect very detailed and extensive lipidomics data. Benefiting from the technological edge, this project gained important insights into the complex process of lipid uptake into the mammalian brain. The findings will be published in scientific journals in a timely manner and the data will be made publicly available.

Publications

• 1-Deoxysphingolipids cause autophagosome and lysosome accumulation and trigger NLRP3 inflammasome activation. Autophagy, 17(8), 1947-1961.
  Lauterbach, Mario A.; Saavedra, Victor; Mangan, Matthew S. J.; Penno, Anke; Thiele, Christoph; Latz, Eicke & Kuerschner, Lars
  
• An advanced method for propargylcholine phospholipid detection by direct-infusion MS. Journal of Lipid Research, 62, 100022.
  Yaghmour, Mohamed H.; Thiele, Christoph & Kuerschner, Lars
  
• Development of oxaalkyne and alkyne fatty acids as novel tracers to study fatty acid beta-oxidation pathways and intermediates. Journal of Lipid Research, 63(4), 100188.
  Kuerschner, Lars; Leyendecker, Philipp; Klizaite, Kristina; Fiedler, Maria; Saam, Jennifer & Thiele, Christoph
  
• Tracing Lipid Metabolism by Alkyne Lipids and Mass Spectrometry: The State of the Art. Frontiers in Molecular Biosciences, 9.
  Kuerschner, Lars & Thiele, Christoph
  
• Sphingomyelin d18:1/14:0 activates TLR4 in metaflammation. Springer Science and Business Media LLC.
  Latz, Eicke; Gorki, Friederike; Dohnalová, Lenka; Thaiss, Christoph; Zurkovic, Jelena; Christ, Anette; Ohto, Umeharu; Marzinek, Jan; Bond, Peter J.; Geißmar, Eike; Singha, Santu; Hamid, Arslan; Yaghmour, Mohamed; de Goede, Kyra; Rothe, Maximilian; Placek, Katarzyna; Polzin, Amin; Wollnitzke, Philipp; Levkau, Bodo ... & Bossche, Jan Van den
  
• Triglyceride cycling enables modification of stored fatty acids. Nature Metabolism, 5(4), 699-709.
  Wunderling, Klaus; Zurkovic, Jelena; Zink, Fabian; Kuerschner, Lars & Thiele, Christoph