Reversal of apoE4-Driven Brain Pathology and Behavioral Deficits by Bexarotene
Reversal of apoE4-Driven Brain Pathology and Behavioral Deficits by Bexarotene
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DOI：
10.1523/jneurosci.5198-13.2014
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发表时间：
2014-05-21
影响因子：
5.3
通讯作者：
Michaelson, Daniel M.
中科院分区：
文献类型：
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作者：
Boehm-Cagan, Anat;Michaelson, Daniel M.
载脂蛋白E4（apoE 4）是阿尔茨海默病（AD）最普遍的遗传危险因子，其脂化程度低于其相应的AD良性形式apoE 3，并且已经表明apoE 4的病理作用是由脂质相关机制介导的。ATP结合盒转运蛋白A1和G1（分别为ABCA 1和ABCG 1）是最重要的载脂蛋白E脂质化蛋白。这些蛋白的表达以及apoE的表达受转录调节类维生素A X受体（RXR）-肝X受体（LXR）系统控制。在本研究中，我们研究了RXR激动剂贝沙罗汀对年轻的、幼稚的apoE 3和apoE 4靶向替代小鼠中apoE、ABCA 1和ABCG 1的mRNA和蛋白水平的影响，并评估了逆转apoE 4驱动的病理表型的程度。本研究发现，贝沙罗汀可增加海马神经元ABCA 1和ABCG 1的mRNA和蛋白水平，但对相应的apoE水平无影响。这些发现与逆转apoE 4的脂质化缺陷和apoE 4小鼠在几项试验中的认知障碍有关。此外，贝沙罗汀逆转了apoE 4驱动的海马神经元中A β 42和过度磷酸化tau蛋白的积累，以及apoE 4诱导的突触前标记物囊泡神经元转运蛋白1（VGluT 1）水平的降低。总之，结果表明，用RXR激动剂贝沙罗汀治疗apoE 4小鼠在体内逆转了apoE 4诱导的认知和神经元损伤，并表明这是由于逆转了apoE 4的脂化缺陷。这提出了RXR激活和ABCA 1和ABCG 1水平增加可能用于治疗人apoE 4携带者的可能性。
Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is less lipidated than its corresponding AD-benign form, apoE3, and it has been suggested that the pathological effects of apoE4 are mediated by lipid-related mechanisms. ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1, respectively) are the most important apoE-lipidating proteins. The expression of these proteins, as well as that of apoE, is controlled by the transcription regulation retinoid X receptor (RXR)-liver X receptor (LXR) system. In the present study, we investigated the effects of the RXR agonist bexarotene on mRNA and protein levels of apoE, ABCA1, and ABCG1 in young, naive apoE3- and apoE4-targeted replacement mice and assessed the extent to which this reverses the apoE4-driven pathological phenotype. This investigation reveled that bexarotene increases the mRNA and protein levels of ABCA1 and ABCG1 in hippocampal neurons, but has no effect on the corresponding levels of apoE. These findings were associated with reversal of the lipidation deficiency of apoE4 and of the cognitive impairments of apoE4 mice in several tests. Furthermore, bexarotene reversed the apoE4-driven accumulation of A beta 42 and hyperphosphorylated tau in hippocampal neurons, as well as the apoE4-induced reduction in the levels of the presynaptic marker vesicular glutamatergic transporter 1 (VGluT1). In conclusion, the results show that treatment of apoE4 mice with the RXR agonist bexarotene reverses the apoE4-induced cognitive and neuronal impairments in vivo and suggest that this is due to reversal of the lipidation deficiency of apoE4. This puts forward the possibility that RXR activation and increased levels of ABCA1 and ABCG1 could be useful in the treatment of human apoE4 carriers.