Chemerin-9 Peptide Enhances Memory and Ameliorates Aβ1-42-Induced Object Memory Impairment in Mice
Chemerin-9 Peptide Enhances Memory and Ameliorates Aβ1-42-Induced Object Memory Impairment in Mice
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DOI：
10.1248/bpb.b19-00510
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发表时间：
2020-02-01
影响因子：
2
通讯作者：
Yu, Qin
中科院分区：
文献类型：
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作者：
Lei, ZeLin;Lu, YaQin;Yu, Qin
越来越多的证据表明，抑制神经炎症是阿尔茨海默病（AD）治疗或预防策略的潜在靶点。Chemerin因其在炎症调节中的作用而引起特别关注。此外，淀粉样蛋白β（1 - 42）（A β（1 - 42））可以与趋化因子样受体1（CMKLR1）（趋化素受体）相互作用，并诱导小胶质细胞趋化性。同时，CMKLR1在大脑中表达，chemerin和A β（1 - 42）共享相同的受体。因此，我们假设chemerin（C9），一种chemerin衍生的九肽，可能具有改善A β（1 - 42）介导的AD疾病进展的潜力。结果表明，侧脑室（i.c.v.）注射C9（8 μ g/kg）促进了记忆形成并改善了记忆保持，如新物体识别测试（NOR）和物体位置识别（OLR）任务的结果所证明的。将C9（2 μ g/kg）注入海马后，也观察到C9的这些记忆增强作用。此外，我们发现用C9处理逆转了由寡聚体A β（1 - 42）诱导的记忆和学习能力的下降。同时，C9还显著抑制A β（1 - 42）诱导的海马中促炎细胞因子如白细胞介素-1 β（IL-1 β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平的增加。Western印迹和酶联免疫吸附试验（ELISA）实验获得了相同的结果。最后，我们观察到C9不影响自发活动，这表明其改善记忆不是由hypolocomotion诱导的假阳性。总之，C9可以促进记忆形成，延长记忆保持，并改善A β（1 - 42）诱导的记忆障碍，这表明C9可能代表治疗AD的新策略。
Accumulating evidence suggests that the inhibition of neuroinflammation is a potential target for therapeutic or preventive strategies for Alzheimer's disease (AD). Chemerin has attracted particular attention for its role in the regulation of inflammation. In addition, amyloid beta(1-42) (A beta(1-42)) can interact with chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, and induce microglial chemotaxis. Meanwhile, CMKLR1 is expressed in the brain, and both chemerin and A beta(1-42) share the same receptor. Thus, we hypothesized that chemerin (C9), a chemerin-derived nonapeptide, may have the potential to ameliorate A beta(1-42) mediated AD disease progression. The results showed that an intracerebroventricular (i.c.v.) injection of C9 (8 mu g/kg) facilitated memory formation and improved memory retention, as evidenced by the results of both the novel object recognition test (NOR) and object location recognition (OLR) tasks. These memory-enhancing effects of C9 were also observed after C9 (2 mu g/kg) was infused into the hippocampus. Moreover, we found that treatment with C9 reversed the de cits in memory and learning ability induced by oligomeric A beta(1-42). Meanwhile, C9 also signi cantly inhibited A beta(1-42)-induced increases in the levels of pro-in ammatory cytokines such as interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the hippocampus. The same results were obtained for Western blotting and enzyme-linked immunosorbent assay (ELISA) experiments. Finally, we observed that C9 did not affect locomotor activity, suggesting that its improvement of memory is not a false positive induced by hypolocomotion. In conclusion, C9 may facilitate memory formation, prolong memory retention, and ameliorate A beta(1-42)-induced memory impairment, suggesting that C9 may potentially represent a novel strategy for the treatment of AD.