Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins
Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins
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DOI：
10.1371/journal.pone.0166195
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发表时间：
2016-11-08
期刊：
影响因子：
3.7
通讯作者：
Michaelson, Daniel M.
中科院分区：
文献类型：
--
作者：
Boehm-Cagen, Anat;Bar, Roni;Michaelson, Daniel M.
载脂蛋白E4（apoE 4）是阿尔茨海默病（AD）的主要遗传危险因素，与最常见的AD良性等位基因apoE 3相比，其脂化程度较低。我们最近发现，apoE小鼠腹腔注射ATP结合盒A1（ABCA 1）激动剂肽CS-6253可逆转apoE 4的低脂化以及相关的脑病理学和行为缺陷。在脑内，apoE是主要的胆固醇转运蛋白，而在外周，apoE和apoA-I都是主要的胆固醇转运蛋白。我们目前研究了apoE基因型和CS-6253治疗apoE 3和apoE 4靶向替代小鼠对apoE血浆水平和脂质颗粒分布以及血浆和脑apoA-I和apoJ水平和脂质颗粒分布的影响程度。这表明，血浆apoE 4水平低于血浆apoE 3，并且在FPLC后洗脱更快。CS-6253处理增加了血浆apoE 4的水平，并使apoE 4的洗脱曲线与apoE 3相似。同样，apoE 4小鼠的血浆apoA-I水平低于apoE 3小鼠，CS-6253可部分逆转该效应。相反，在apoE 4小鼠中较高的脑中apoA-I水平不受CS-6253的影响。apoE 4小鼠的apoJ血浆水平高于apoE 3小鼠，CS-6253可消除该效应。在大脑中获得了类似但不太明显的效果。总之，这些结果表明，apoE 4影响apoA-I和apoJ的水平，CS-6253的抗apoE 4有益作用可能与中枢和外周机制有关。
Apolipoprotein E4 (apoE4), the leading genetic risk factor for Alzheimer's disease (AD), is less lipidated compared to the most common and AD-benign allele, apoE3. We have recently shown that i.p. injections of the ATP-binding cassette A1 (ABCA1) agonist peptide CS-6253 to apoE mice reverse the hypolipidation of apoE4 and the associated brain pathology and behavioral deficits. While in the brain apoE is the main cholesterol transporter, in the periphery apoE and apoA-I both serve as the major cholesterol transporters. We presently investigated the extent to which apoE genotype and CS-6253 treatment to apoE3 and apoE4-targeted replacement mice affects the plasma levels and lipid particle distribution of apoE, and those of plasma and brain apoA-I and apoJ. This revealed that plasma levels of apoE4 were lower and eluted faster following FPLC than plasma apoE3. Treatment with CS-6253 increased the levels of plasma apoE4 and rendered the elution profile of apoE4 similar to that of apoE3. Similarly, the levels of plasma apoA-I were lower in the apoE4 mice compared to apoE3 mice, and this effect was partially reversed by CS-6253. Conversely, the levels of apoA-I in the brain which were higher in the apoE4 mice, were unaffected by CS-6253. The plasma levels of apoJ were higher in apoE4 mice than apoE3 mice and this effect was abolished by CS-6253. Similar but less pronounced effects were obtained in the brain. In conclusion, these results suggest that apoE4 affects the levels of apoA-I and apoJ and that the anti-apoE4 beneficial effects of CS-6253 may be related to both central and peripheral mechanisms.