Background:Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr–/–), a mousemodel of familial hypercholesterolemia. Objective:Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr–/–mice. Methods:Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/–mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi. Results:A tenfold elevation in plasma cholesterol levels of LDLr–/–mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr–/–mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr–/–mice treated with a hypercholesterolemic diet. The LDLr–/–mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr–/–mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice. Conclusion:Therefore, LDLr–/–mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.

中文翻译：

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高胆固醇饮食会加剧 LDLr-/- 小鼠的血脑屏障破坏：对认知功能的影响。

背景：有证据表明家族性高胆固醇血症与认知障碍之间存在关联。在这方面，在低密度脂蛋白受体敲除小鼠 (LDLr–/–)（一种家族性高胆固醇血症小鼠模型）中发现认知缺陷与海马血脑屏障 (BBB) 破坏之间存在联系。目的：在此我们研究了高胆固醇血症饮食对 C57BL/6 野生型和 LDLr–/– 小鼠认知和 BBB 功能的影响。方法：用正常或高胆固醇饮食喂养动物30天。因此，野生型和 LDLr–/– 小鼠被提交给记忆范式。此外，在小鼠的前额叶皮质和海马中评估了 BBB 的完整性。结果：在高胆固醇血症饮食后观察到 LDLr–/– 小鼠的血浆胆固醇水平升高了 10 倍，而在野生型小鼠中，高胆固醇饮食暴露仅适度增加血浆胆固醇水平，不会引起认知障碍。无论饮食如何，LDLr–/– 小鼠均表现出记忆障碍。我们观察到 BBB 破坏是由于前额叶皮质和海马中荧光素钠的通透性增加，以及用高胆固醇饮食治疗的野生型和 LDLr–/– 小鼠的海马 claudin-5 和 occludin mRNA 水平降低。用常规饮食喂养的 LDLr–/– 小鼠已经出现 BBB 功能障碍。LDLr–/– 小鼠海马中 BBB 增加的渗漏与高微血管含量和强烈的星形胶质细胞增生有关，而这在对照小鼠中没有发生。结论：因此，LDLr–/– 小鼠似乎更容易受到高胆固醇饮食引起的认知障碍和 BBB 损伤的影响。最后，血脑屏障破坏似乎是高胆固醇血症引起的大脑改变的相关事件。