Journal
AGING-US
Volume 12, Issue 21, Pages 22266-22290Publisher
IMPACT JOURNALS LLC
Keywords
Naked mole-rat; neurodegeneration; amyloid beta; brain; lipidomics
Categories
Funding
- EPSRC Underpinning Multi-User Equipment Call [EP/P030467/1]
- National Science Foundation [1655494]
- UIC DFI Fellowship
- Cancer Research UK/RCUK [C56829/A22053]
- Dunhill Medical Trust [RPGF2002\188]
- BBSRC-DTP studentship
- Centre for Misfolding Diseases
- Agence Nationale de la Recherche [ANR-18-CE14-0039-01]
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [1655494] Funding Source: National Science Foundation
- EPSRC [EP/P030467/1] Funding Source: UKRI
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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 (A8) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against A8 neurotoxicity. Here we examine the composition, phase behaviour, and A8 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 A8 disrupts naked mole-rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon A8 exposure.
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