This narrative review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment and dementia (VCID). Humans have a peripheral lipoprotein profile where low-density lipoproteins (LDL) represent the dominant lipoprotein fraction and high-density lipoproteins (HDL) represent a minor lipoprotein fraction. Elevated LDL-cholesterol (LDL-C) levels are well-established to cause cardiovascular disease and several LDL-C-lowering therapies are clinically available to manage this vascular risk factor. The efficacy of LDL-C-lowering therapies to reduce risk of all-cause dementia and AD is now important to address as recent studies demonstrate a role for LDL in Alzheimer’s Disease (AD) as well as in all-cause dementia. The LDL:HDL ratio in humans is set mainly by CETP activity, which exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise LDL and lower HDL as CETP activity increases. Genetic and pharmacological studies support the hypothesis that CETP inhibition reduces cardiovascular risk by lowering LDL, which, by extension, may also lower VCID. Unlike humans, wild-type mice do not express catalytically active CETP and have HDL as their major lipoprotein fraction. As HDL has potent beneficial effects on endothelial cells, the naturally high HDL levels in mice protect them from vascular disorders, likely including VCID. Genetic restoration of CETP expression in mice to generate a more human-like lipid profile may increase the relevance of murine models for VCID studies. The therapeutic potential of existing and emerging LDL-lowering therapies for VCID will be discussed. Figure Legend. Cholesteryl Ester Transfer Protein in Alzheimer’s Disease. CETP is mainly produced by the liver, and exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise circulating LDL and lower HDL as CETP activity increases. Low CETP activity is associated with better cardiovascular health, due to decreased LDL and increased HDL, which may also improve brain health. Although most peripheral lipoproteins cannot enter the brain parenchyma due to the BBB, it is increasingly appreciated that direct access to the vascular endothelium may enable peripheral lipoproteins to have indirect effects on brain health. Thus, lipoproteins may affect the cerebrovasculature from both sides of the BBB. Recent studies show an association between elevated plasma LDL, a well-known cardiovascular risk factor, and a higher risk of AD, and considerable evidence suggests that high HDL levels are associated with reduced CAA and lower neuroinflammation. Considering the potential detrimental role of LDL in AD and the importance of HDL’s beneficial effects on endothelial cells, high CETP activity may lead to compromised BBB integrity, increased CAA deposits and greater neuroinflammation. Abbreviations: CETP – cholesteryl transfer ester protein; LDL – low-density lipoproteins; HDL – high-density lipoproteins; BBB – blood-brain barrier; CAA – cerebral amyloid angiopathy, SMC – smooth muscle cells, PVM – perivascular macrophages, RBC – red blood cells.

中文翻译：

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外周脂蛋白和胆固醇酯转移蛋白在认知障碍和痴呆的血管贡献中的作用

这篇叙述性综述的重点是胆固醇酯转移蛋白 (CETP) 和外周脂蛋白在血管导致认知障碍和痴呆 (VCID) 中的作用。人类具有外周脂蛋白谱，其中低密度脂蛋白（LDL）代表主要脂蛋白部分，高密度脂蛋白（HDL）代表次要脂蛋白部分。众所周知，低密度脂蛋白胆固醇 (LDL-C) 水平升高会导致心血管疾病，临床上有几种降低低密度脂蛋白胆固醇 (LDL-C) 的疗法可用于控制这一血管危险因素。降低 LDL-C 疗法降低全因痴呆和 AD 风险的功效现在非常重要，因为最近的研究表明 LDL 在阿尔茨海默病 (AD) 以及全因痴呆中发挥着作用。人体中的 LDL:HDL 比率主要由 CETP 活性决定，CETP 活性将脂蛋白部分中的胆固醇酯交换为甘油三酯，从而随着 CETP 活性的增加而升高 LDL 并降低 HDL。遗传和药理学研究支持这样的假设：CETP 抑制通过降低 LDL 来降低心血管风险，进而降低 VCID。与人类不同，野生型小鼠不表达具有催化活性的 CETP，并且以高密度脂蛋白 (HDL) 作为其主要脂蛋白成分。由于 HDL 对内皮细胞具有有效的有益作用，因此小鼠体内天然的高 HDL 水平可以保护它们免受血管疾病（可能包括 VCID）的影响。在小鼠中对 CETP 表达进行基因恢复以产生更像人类的脂质谱可能会增加小鼠模型与 VCID 研究的相关性。将讨论现有和新兴的 VCID 降低 LDL 疗法的治疗潜力。图例。阿尔茨海默病中的胆固醇酯转移蛋白。CETP 主要由肝脏产生，并通过脂蛋白部分将胆固醇酯交换为甘油三酯，从而随着 CETP 活性的增加而升高循环 LDL 并降低 HDL。由于低密度脂蛋白降低和高密度脂蛋白增加，低 CETP 活性与更好的心血管健康相关，这也可能改善大脑健康。尽管大多数外周脂蛋白由于血脑屏障而无法进入脑实质，但人们越来越认识到，直接进入血管内皮可能使外周脂蛋白对大脑健康产生间接影响。因此，脂蛋白可能影响血脑屏障两侧的脑血管系统。最近的研究表明，血浆 LDL 升高（众所周知的心血管危险因素）与 AD 风险升高之间存在关联，并且大量证据表明，高 HDL 水平与 CAA 减少和神经炎症降低相关。考虑到 LDL 在 AD 中的潜在有害作用以及 HDL 对内皮细胞有益作用的重要性，高 CETP 活性可能会导致 BBB 完整性受损、CAA 沉积增加和更严重的神经炎症。缩写：CETP——胆固醇转移酯蛋白；LDL——低密度脂蛋白；HDL——高密度脂蛋白；BBB——血脑屏障；CAA – 脑淀粉样血管病，SMC – 平滑肌细胞，PVM – 血管周围巨噬细胞，RBC – 红细胞。