ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations
ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations
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DOI：
10.1038/npp.2015.95
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发表时间：
2015-09-01
影响因子：
7.6
通讯作者：
Raber, Jacob
中科院分区：
文献类型：
--
作者：
Johnson, Lance A.;Zuloaga, Damian G.;Raber, Jacob
载脂蛋白E （apoE）是大脑和外周脂蛋白颗粒的重要组成部分，在人群中存在三种亚型：E2， E3和E4。载脂蛋白e在神经生物学中有许多明确的作用。最值得注意的是，E4与阿尔茨海默病（AD）的早期发病和风险增加有关。虽然拥有E2对AD具有保护作用，但E2似乎会增加创伤后应激障碍（PTSD）的发病率和严重程度。然而，这种联系背后的生物学过程仍不清楚。在这项研究中，我们通过研究apoE对退伍军人PTSD严重程度的影响，以及对携带人类apoE的小鼠PTSD样行为的影响，开始阐明这些关联。在一组92名患有PTSD的退伍军人中，我们观察到E2+个体的临床管理PTSD量表和PTSD检查表得分明显较高，唾液皮质醇水平也有所改变。此外，我们测量了在单一应激事件后表达人类apoE的小鼠的行为和生物学结果，以及在一段时间的慢性可变应激（一种与战斗相关的创伤模型）之后。E2小鼠在创伤后表现出恐惧消退、行为、认知和神经内分泌的损伤。据我们所知，这些数据构成了男性PTSD严重程度和E2小鼠PTSD样症状的第一个转化证明，并指出apoE是PTSD易感性的新生物标志物和潜在的治疗靶点。
Apolipoprotein E (apoE) is an essential component of lipoprotein particles in both the brain and periphery, and exists in three isoforms in the human population: E2, E3, and E4. ApoE has numerous, well-established roles in neurobiology. Most notably, E4 is associated with earlier onset and increased risk of Alzheimer's disease (AD). Although possession of E2 is protective in the context of AD, E2 appears to confer an increased incidence and severity of posttraumatic stress disorder (PTSD). However, the biological processes underlying this link remain unclear. In this study, we began to elucidate these associations by examining the effects of apoE on PTSD severity in combat veterans, and on PTSD-like behavior in mice with human apoE. In a group of 92 veterans with PTSD, we observed significantly higher Clinician-Administered PTSD Scale and PTSD Checklist scores in E2+ individuals, as well as alterations in salivary cortisol levels. Furthermore, we measured behavioral and biological outcomes in mice expressing human apoE after a single stressful event as well as following a period of chronic variable stress, a model of combat-related trauma. Mice with E2 showed impairments in fear extinction, and behavioral, cognitive, and neuroendocrine alterations following trauma. To the best of our knowledge, these data constitute the first translational demonstration of PTSD severity in men and PTSD-like symptoms in mice with E2, and point to apoE as a novel biomarker of susceptibility, and potential therapeutic target, for PTSD.