Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage

Abstract

Naked mole-rats do not develop neurodegenerative diseases associated with ageing and their brains are devoid of amyloid plaques. However, even the young naked mole-rat brain contains high concentrations of amyloid beta peptide. Thus, the question arises, how do naked mole-rat brain cell membranes survive in this amyloid rich environment? In this work 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 less sphingomyelin, the sphingomyelin present being of a characteristic short chain length. We find that naked mole-rat brain lipid membranes exhibit an extremely high degree of phase separation, consistent with the membrane pacemaker hypothesis of ageing, with the liquid ordered phase occupying up to 80 % of the supported lipid bilayer. Exposure of mouse brain lipids to human amyloid beta at physiologically relevant concentrations leads to small, well-defined "footprints", whereby the amyloid beta has sunk into the membrane. Under the same exposure regime, the naked mole-rat brain lipid membranes are destroyed, leaving only membrane fragments in place of the intact membrane. These results suggest that naked mole-rats have likely developed additional neuroprotective mechanisms to limit cellular damage because by considering lipids alone brain tissue should not be able to survive in such a toxic environment.

Phylogenetic modeling of enhancer shifts in African mole-rats reveals regulatory changes associated with tissue-specific traits

“…Although we detect a lower number of associated loci in the single-species branch, these include both upstream (Insr) and downstream (Foxo1) response genes, suggesting specific regulatory changes in this response in Damaraland mole-rat. Similarly, we found loci associated to ceramide biosynthesis in Up liver enhancers for both the ancestral and naked mole-rat branches (Figure 4D), which is consistent with reported high levels of short-chain ceramides in naked mole-rat brain lipids [46]. Lastly, we detected genomic loci associated with the response to hypoxia among heart enhancer shifts both in ancestral and naked mole-rat branches (Figure 4A and 4E).…”