Apelin-13 Suppresses Neuroinflammation Against Cognitive Deficit in a Streptozotocin-Induced Rat Model of Alzheimer's Disease Through Activation of BDNF-TrkB Signaling Pathway
Apelin-13 Suppresses Neuroinflammation Against Cognitive Deficit in a Streptozotocin-Induced Rat Model of Alzheimer's Disease Through Activation of BDNF-TrkB Signaling Pathway
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Apelin-13 通过激活 BDNF-TrkB 信号通路抑制链脲佐菌素诱导的阿尔茨海默病大鼠模型中的神经炎症和认知缺陷
DOI：
10.3389/fphar.2019.00395
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发表时间：
2019-04-16
影响因子：
5.6
通讯作者：
Qin, Xiaoqun
中科院分区：
文献类型：
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作者：
Luo, Huaiqing;Xiang, Yang;Qin, Xiaoqun
阿尔茨海默病(AD)是一种进行性神经退行性疾病，其特征是由于突触缺陷和神经元丢失而导致认知功能受损，与炎症有关。Apelin-13是一种主要的神经肽，具有抑制炎症的作用，对认知记忆和神经元损伤具有有益的作用。然而，apelin-13是否能通过抑制炎症反应来保护神经元以改善AD患者的认知障碍仍是一个很大的未知数。为了验证这一假说，大鼠脑室注射链脲佐菌素(3 mg/kg)或与apelin-13(2 mg/g)联合注射。注射apelin前10min给予酪氨酸受体激酶B(TrkB)阻断剂K252a(200 NM)。此外，通过新对象识别(NOR)和Y迷宫测试来评估认知能力。用免疫印迹和免疫组织化学方法检测APELIN、APJ、小胶质细胞标记物(IBA1)、星形胶质细胞标记物(GFAP)、白介素1β(IL-β)、肿瘤坏死因子-α(TNF-α)、突触素(Sw)、脑源性神经营养因子(BDNF)、TrkB、磷酸化TrkB(p-TrkB)在海马区的表达。用实时定量聚合酶链式反应(PCR)检测IBA1、GFAP、IL-1β、TNF-α、SYP基因表达。苏木精-伊红(H&E)染色检测海马炎性改变。采用酶联免疫吸附试验(ELISA)检测乙酰胆碱的表达水平。乙酰胆碱酯酶检测试剂盒检测乙酰胆碱酯酶活性。我们观察到给予链脲佐菌素的大鼠海马区APELIN/APJ信号下调。Apelin-13可显著改善STZ诱导的AD样表型，包括认知障碍、胆碱能功能障碍以及神经元和突触可塑性的损伤。此外，Apelin-13还能抑制AD大鼠小胶质细胞和星形胶质细胞的激活，减少IL-1β和TNF-α的表达，减少海马区BDNF/TrkB的表达缺失。TrkB受体拮抗剂K252a可阻断apelin-13的作用。这些结果表明，apelin-13通过减轻炎症，上调BDNF/TrkB通路，对抗STZ诱导的散发性AD大鼠的认知障碍。
Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by impairments of cognitive function as a result of synaptic deficits and neuronal loss, is associated with inflammation. Apelin-13, a predominant neuropeptide with inhibiting effect on inflammation, has beneficial effects on cognition memory and neuronal damage. However, whether apelin-13 can protect neurons to ameliorate cognitive deficits in AD by inhibiting the inflammatory response remains largely unknown. To test this hypothesis, rats were intracerebroventricularly (ICV) injected with streptozotocin (3 mg/kg) alone or in combination with apelin-13 (2 mu g). And tyrosine receptor kinase B (TrkB) blocker K252a (200 nM) was administrated 10 min before apelin injection. Furthermore, cognitive performance was assessed by new object recognition (NOR) and Y-maze tests. Protein expression of apelin, APJ, microglial marker (IBA1), astroglia marker (GFAP), interleukin 1 beta (IL-beta), tumor necrosis factor-alpha (TNF-alpha), synaptophysin (SW), brain-derived neurotrophic factor (BDNF), TrkB, phospho-TrkB (p-TrkB) in the hippocampus were examined by western blotting or immunohistochemistry. And the gene expression of IBA1, GFAP, IL-1 beta, TNF-alpha, and SYP were detected by real-time quantitative polymerase chain reaction (PCR). Inflammatory disorder in the hippocampus was tested by hematoxylin and eosin (H&E) staining. The enzyme-linked immunosorbent assay (ELISA) was used to study the expression level of acetylcholine. And the activity of acetylcholinesterase was detected by Acetylcholinesterase Assay Kit. We observed that apelin/APJ signaling was downregulated in the hippocampus of rats administrated with STZ. Apelin-13 was found to significantly ameliorate STZ-induced AD-like phenotypes including congnitive deficit, cholinergic disfunction and the damage of neuron and synaptic plasticity. Moreover, apelin-13 inhibited microglia and astrocyte activation, reduced IL-1 beta and TNF-alpha expression and hippocampal BDNF/TrkB expression deficit in AD rats. Finally, apelin-13-mediated effects were blocked by TrkB receptor antagonist K252a. These results suggest that apelin-13 upregulates BDNF/TrkB pathway against cognitive deficit in a STZ-induced rat model of sporadic AD by attenuating inflammation.