Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP Endothelial KnockOut (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared to control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased GSK3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased GSK3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice.

中文翻译：

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内皮醚脂质将脉管系统与血压、行为和神经变性联系起来。

血管疾病会导致神经退行性变，这与老年人的血压下降有关。缩醛磷脂，即过氧化物酶体产生的醚磷脂，在阿尔茨海默病、帕金森病和其他神经退行性疾病中减少。然而，醚磷脂、血压和神经退行性变之间的机制联系尚不完全清楚。在这里，我们表明内皮衍生的醚磷脂会影响小鼠的血压、行为和神经退行性变。在年轻的成年小鼠中，PexRAP（一种醚脂质合成所需的过氧化物酶体酶）的可诱导内皮特异性破坏意外地减少了循环缩醛磷脂。PexRAP 内皮敲除 (PEKO) 小鼠对后肢缺血反应正常，但血压降低，血浆肾素活性增加。在 PEKO 中，与对照小鼠相比，蓝斑中的酪氨酸羟化酶降低，从而维持血压和觉醒。PEKO 小鼠活动较少，睡眠较多，并且对环境事件的注意力和回忆受损以及轻度空间记忆缺陷。在 PEKO 海马中，神经胶质增生增加，与记忆相关的缩醛磷脂减少。尽管血压较低，但通过大脑皮层的光学神经成像，PEKO 小鼠通常具有正常的同位功能连接。在 PEKO 大脑皮层中检测到 GSK3 磷酸化降低，这是神经变性的标志物。在共培养系统中，脑内皮细胞中的 PexRAP 敲低降低了共培养的星形胶质细胞中的 GSK3 磷酸化，这些星形胶质细胞通过与醚脂质烷基甘油孵育而得以挽救。综合起来，