ORM Elevation in Response to Cognitive Impairment Is an Accompanying Phenomenon
ORM Elevation in Response to Cognitive Impairment Is an Accompanying Phenomenon
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DOI：
10.1111/cns.12586
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发表时间：
2016-08
影响因子：
5.5
通讯作者：
Jing-jing Wan;Z. Qin;Xia Liu
中科院分区：
文献类型：
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作者：
Jing-jing Wan;Z. Qin;Xia Liu
学习记忆障碍是认知功能障碍的特征，常见于阿尔茨海默病、脑卒中、抑郁症、慢性疲劳综合征（CFS）等患者[1]。认知障碍已成为现代社会中最大的健康威胁之一，而包括胆碱酯酶抑制剂、维生素E、抗抑郁药或其他可能具有改善疾病作用的化合物在内的药物仅具有负面、轻微或适度的作用。仍然需要开发针对此类病症的新的治疗靶标。ORM是一种急性时相蛋白，pI非常低，为2.8-3.8，碳水化合物含量非常高，为45%。在人类中有两种ORM亚型（ORM 1和ORM 2），在小鼠中有三种亚型（ORM 1，ORM 2和ORM 3）。ORM 1的组成水平是主要亚型，并且只有ORM 1可以被急性期刺激诱导。ORM具有多种生物学活性，包括调节免疫、介导鞘脂代谢、携带药物以及作为疾病标志物[2]。近年来，许多研究表明ORM可能参与认知功能的调节。ORM在CFS患者血清[3]、斯托克小鼠脑组织[4]、抑郁患者血清[5]和HIV相关神经认知障碍患者脑脊液[6]中显著升高。特别是，据报道ORM介导鞘脂的代谢[7]，而脑脊液中鞘脂含量的紊乱与HIV感染患者的记忆障碍有关[8]。此外，研究表明，热量限制通过防止大脑中的鞘脂周转失调来改善老年人以及帕金森病和阿尔茨海默病动物模型的认知功能[9]。所有这些研究都促使我们调查ORM除了作为一个指示性标志物外，是否还可以影响认知功能。我们首先评估了ORM对学习和记忆能力的物理影响。ORM 1敲除小鼠在我们的实验室中产生，如先前报道的[10]。采用Morris水迷宫（MWM）检测大鼠的空间学习记忆能力。出乎意料的是，无论是平台的平均潜伏期还是平均值图1内源性ORM对小鼠在Morris水迷宫测试中的表现的影响。使用ORM 1 +/+和ORM 1/小鼠来评价内源性ORM对认知功能的影响。(A)连续4天，每天4次试验的平台平均延迟。(B)第5天平均穿越平台次数。(C)第5天去除平台后小鼠的代表性游泳路径。绿色圆圈表示平台的先前位置。数据表示为平均SEM，并通过学生t检验进行分析。每组N = 5-7。P < 0.05为有统计学意义。
Learning and memory deficit is the characteristic of cognitive impairment, which is often seen in patients with Alzheimer’s disease, stroke, depression, chronic fatigue syndrome (CFS), and so on [1]. Cognitive impairment has emerged as one of the greatest health threats in the modern society, and drugs including cholinesterase inhibitors, vitamin E, antiinflammatory drugs, or other compounds with possible disease-modifying effects, have only negative, minor or modest effects. Developing new therapeutic targets for such conditions is still needed. ORM is an acute-phase protein, with very low pI of 2.8–3.8 and a very high carbohydrate content of 45%. There are two isoforms of ORM in humans (ORM1 and ORM2) and three isoforms in mice (ORM1, ORM2, and ORM3). Constitutive level of ORM1 is the dominant isoform, and only ORM1 can be induced by acute-phase stimuli. Many biological activities of ORM have been identified, including modulating immunity, mediating the sphingolipid metabolism, carrying drugs, and also acting as a disease marker [2]. Recently, many reports indicate that ORM may be involved in the regulation of cognitive function. ORM is significantly elevated in the serum of patients with CFS [3], brain tissues of stoke mice [4], sera of the depressed patients [5], and cerebral spinal fluid of the patients with HIV-associated neurocognitive impairment [6]. Especially, ORM is reported to mediate the metabolism of sphingolipid [7], while the disturbance of sphingolipid content in cerebral spinal fluid is associated with memory impairment in patients infected with the HIV [8]. Moreover, studies have demonstrated that calorie restriction improved cognitive function at old age and in animal models of Parkinson’s and Alzheimer’s disease via preventing the sphingolipid turnover dysregulation in the brain [9]. All of these studies prompt us to investigate whether ORM could affect cognitive function in addition to acting as an indicative marker. We first evaluated the physical effect of ORM on the ability to learn and remember. ORM1 knocked-out mice were generated in our laboratory as previously reported [10]. The Morris water maze (MWM) test was applied to investigate spatial learning and memory. Unexpectedly, neither average latency to platform nor mean Figure 1 The effect of endogenous ORM on the performance of mice in Morris water maze testing. ORM1+/+ and ORM1 / mice were used to evaluate the effect of endogenous ORM on the cognitive function. (A) Average latency to platform of 4 trials per day for the consecutive 4 days. (B) Mean number of platform crossing on the 5th day. (C) Representative swim path of mice after platform is removed on the 5th day. Green circle indicates the previous location of platform. Data are presented as mean SEM and analyzed by Student’s t-test. N = 5–7 per group. P < 0.05 was considered statistically significant.