Department of Behavioral Neuroscience, Oregon Health & Science University, 3181SW Sam Jackson Park Road, L470, Portland, OR, 97239, USA.
Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA.
Transl Psychiatry. 2022 Mar 28;12(1):125. doi: 10.1038/s41398-022-01848-7.
Post-Traumatic Stress Disorder (PTSD) is a highly prevalent mental health disorder. Due to the high level of variability in susceptibility and severity, PTSD therapies are still insufficient. In addition to environmental exposures, genetic risks play a prominent role and one such factor is apolipoprotein E. The protein (apoE) is functionally involved in cholesterol transport and metabolism and exists as 3 major isoforms in humans: E2, E3, and E4. To model the role of apolipoprotein E isoform in stress-related changes in behavior and cognition, female and male mice (3-5 months of age) expressing E2, E3, or E4 were used. Mice were either placed into control groups or exposed to chronic variable stress (CVS), which has been shown to induce PTSD-like behavioral and neuroendocrine changes. E2 mice showed a unique response to CVS compared to E3 and E4 mice that included impaired spatial learning and memory, increased adrenal gland weight, and no increase in glucocorticoid receptor protein levels (normalized to apoE levels). In addition, the cholesterol metabolite 7-ketocholesterol was elevated in the cortex after CVS in E3 and E4, but not E2 female mice. E2 confers unique changes in behavioral, cognitive, and biomarker profiles after stress exposure and identify 7-ketocholesterol as a possible novel biomarker of the traumatic stress response. We further explored the relationship between E2 and PTSD in an understudied population by genotyping 102 patients of Cambodian and Vietnamese ethnicity. E2 carriers demonstrated a higher odds ratio of having a PTSD diagnosis compared to E3/E3 carriers, supporting that the E2 genotype is associated with PTSD diagnosis after trauma exposure in this population.
创伤后应激障碍（PTSD）是一种高发的心理健康障碍。由于易感性和严重程度的高度可变性，PTSD 疗法仍然不足。除了环境暴露外，遗传风险也起着重要作用，其中一个因素是载脂蛋白 E。该蛋白（apoE）在胆固醇转运和代谢中具有功能作用，在人类中存在 3 种主要的同工型：E2、E3 和 E4。为了模拟载脂蛋白 E 同工型在与应激相关的行为和认知变化中的作用，使用表达 E2、E3 或 E4 的雌性和雄性小鼠（3-5 个月大）来建模。将小鼠置于对照组或慢性可变应激（CVS）中，CVS 已被证明会引起 PTSD 样的行为和神经内分泌变化。与 E3 和 E4 小鼠相比，E2 小鼠对 CVS 表现出独特的反应，包括空间学习和记忆受损、肾上腺重量增加，以及糖皮质激素受体蛋白水平（与 apoE 水平归一化）没有增加。此外，在 CVS 后，E3 和 E4 但不是 E2 雌性小鼠的皮质中胆固醇代谢物 7-酮胆固醇升高。E2 在应激暴露后赋予行为、认知和生物标志物特征的独特变化，并将 7-酮胆固醇鉴定为创伤应激反应的一个可能的新型生物标志物。我们通过对 102 名柬埔寨和越南血统的患者进行基因分型，进一步在一个研究较少的人群中探讨了 E2 和 PTSD 之间的关系。与 E3/E3 携带者相比，E2 携带者发生 PTSD 诊断的比值比更高，这支持 E2 基因型与该人群创伤后暴露后 PTSD 诊断相关。
