Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage
Résumé
Naked mole-rats are extraordinarily long-lived rodents that do not develop age-related
neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their
brains contain high concentrations of amyloid beta peptide, even from a young age Therefore, these
animals offer an opportunity to investigate mechanisms of resistance against the neurotoxicity of
amyloid beta aggregation. Working in this direction, here we examine the composition, phase
behaviour, and amyloid beta 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 metabolism of ceramides, sphingomyelin and ceramide
receptor activity 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 occupying up 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. However, we found that
exposure to amyloid beta disrupts the naked mole-rat brain lipid membranes while those formed from
mouse brain lipids exhibit small, well-defined footprints, whereby the amyloid beta penetrates deeply
into the lipid membranes. These results suggest that in naked mole-rats the lipid composition of cell
membranes may offer neuroprotection through resistance to oxidative processes rather than through
mechanical effects.
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