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.

中文翻译：

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来自裸鼠痣脑脂质的脂质膜富含胆固醇，高度分离，并且对淀粉样蛋白诱导的损伤敏感

裸mole鼠是长寿命的啮齿动物，不会发展与年龄有关的神经退行性疾病。值得注意的是，即使他们的大脑即使从很小的时候就含有高浓度的淀粉样蛋白β肽，它们也不会积聚淀粉样蛋白斑块。因此，这些动物提供了研究抵抗淀粉样蛋白β聚集体神经毒性的机制的机会。在这个方向上工作，在这里我们检查裸鼠-鼠脑脂质的组成，相行为和淀粉样β相互作用。相对于小鼠，裸鼠痣脑脂质富含胆固醇，且含有鞘磷脂的含量较低，链长较短。在裸mole鼠脑裂解物中，与神经酰胺，鞘磷脂和神经酰胺受体活性相关的蛋白质也被发现减少。相应地，我们发现裸mole鼠脑脂质膜表现出高度的相分离，液相有序相最多占支持的脂质双层的80％。这些观察结果与膜起搏器衰老假说相符，根据该假说，长寿物种具有特别耐氧化损伤的脂质膜。但是，我们发现暴露于淀粉样蛋白β会破坏裸露的rat鼠脑脂质膜，而由小鼠脑脂质形成的淀粉样膜则显示出细小的，清晰界定的足迹，从而淀粉样β分子会深入渗透到脂质膜中。这些结果表明，在裸鼠体内，细胞膜的脂质成分可能通过对氧化过程的抵抗而不是通过机械作用来提供神经保护作用。我们发现裸mole鼠脑脂质膜表现出高度的相分离，液相有序相占据了高达80％的支持脂质双层。这些观察结果与膜起搏器衰老假说相符，根据该假说，长寿物种具有特别耐氧化损伤的脂质膜。但是，我们发现暴露于淀粉样蛋白β会破坏裸露的rat鼠脑脂质膜，而由小鼠脑脂质形成的淀粉样膜则显示出细小的，清晰界定的足迹，从而淀粉样β分子会深入渗透到脂质膜中。这些结果表明，在裸鼠体内，细胞膜的脂质成分可能通过对氧化过程的抵抗而不是通过机械作用来提供神经保护作用。我们发现裸mole鼠脑脂质膜表现出高度的相分离，液相有序相占据了高达80％的支持脂质双层。这些观察结果与膜起搏器衰老假说相符，根据该假说，长寿物种具有特别耐氧化损伤的脂质膜。但是，我们发现暴露于淀粉样蛋白β会破坏裸露的mole鼠脑脂质膜，而由小鼠脑脂质形成的淀粉样膜则显示出细小且轮廓分明的印迹，从而使β淀粉样蛋白深入渗透到脂质膜中。这些结果表明，在裸鼠体内，细胞膜的脂质成分可能通过对氧化过程的抵抗而不是通过机械作用来提供神经保护作用。