Research Paper Volume 12, Issue 21 pp 22266—22290
Cholesterol-rich naked mole-rat brain lipid membranes are susceptible to amyloid beta-induced damage in vitro
- 1 School of Engineering, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK
- 2 Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK
- 3 MetaToulLipidomics Facility, INSERM UMR1048, Toulouse, France
- 4 Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA
- 5 Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK
- 6 Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
- 7 Translational and Clinical Research Institute, Newcastle University, Paul O’Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
- 8 IRSD, INSERM, INRA, INP-ENVT, Toulouse University 3 Paul Sabatier, Toulouse, France
Received: August 3, 2020 Accepted: October 3, 2020 Published: November 4, 2020https://doi.org/10.18632/aging.202138
How to Cite
Copyright: © 2020 Frankel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Naked mole-rats are extraordinarily long-lived rodents that offer unique opportunities to study the molecular origins of age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta (Aβ) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against Aβ neurotoxicity. Here we examine the composition, phase behaviour, and Aβ interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with the metabolism of ceramides, sphingomyelins and sphingosine-1-phosphate receptor 1 were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase extending to 80% of the supported lipid bilayer. These observations are consistent with the ‘membrane pacemaker’ hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. We also found that exposure to Aβ disrupts naked mole-rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon Aβ exposure.