<br>Synapsin 1 可改善阿尔茨海默病大鼠的认知障碍和神经炎症：一项实验和生物信息学研究,Current Alzheimer Research

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Synapsin 1 可改善阿尔茨海默病大鼠的认知障碍和神经炎症：一项实验和生物信息学研究
Current Alzheimer Research ( IF 1.8 ) Pub Date : 2024-01-12 , DOI: 10.2174/0115672050276594231229050906
Wei Ma ₁ , Kui Lu ₂ , Hua-Min Liang ₁ , Jin-Yuan Zhang ₁

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背景::: 阿尔茨海默病 (AD) 是一种持续性神经病理损伤，表现为神经元/突触死亡、老年斑发展、tau 蛋白过度磷酸化、神经炎症和细胞凋亡。突触蛋白 1 (SYN1) 是一种神经元磷蛋白，被认为与 AD 的病理学有关。目的：本研究旨在阐明 SYN1 在改善 AD 中的确切作用及其潜在的调节机制。方法：从GEO数据库下载AD数据集GSE48350，SYN1侧重于差异表达分析和基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析。建立 AD 大鼠模型后，用 RNAi 慢病毒处理以触发 SYN1 过表达。通过多项实验（水迷宫测试和物体识别测试）验证了 SYN1 对 AD 相关行为的改善作用。通过检测炎症因子（白细胞介素（IL）-6、IL-1β、肿瘤坏死因子（TNF）-α）、神经递质（乙酰胆碱（ACh）、多巴胺（DA）浓度，证实SYN1对AD重要因子的修复作用）、5-羟色氨酸（5-HT））和氧化应激标记物（谷胱甘肽（GSH）、丙二醛（MDA）、活性氧（ROS））。进行分子生物学实验（qRT-PCR 和蛋白质印迹）来检查 SYN1 过表达后 AD 相关的信号通路。结果：差异表达分析共获得545个差异表达基因，其中4个上调，541个下调。富集的通路基本集中于突触功能，蛋白质-蛋白质相互作用网络的分析则集中于SYN1中的关键基因。 SYN1显着改善AD大鼠的空间学习和记忆能力。这种增强反映在大鼠在水迷宫中的逃避潜伏期缩短、在第三象限的停留时间显着延长以及穿越次数增加。此外，物体识别测试的结果显示，老鼠探索熟悉和新物体的时间减少了。 SYN1过表达后，cAMP信号通路被激活，CREB和PKA蛋白磷酸化水平升高，促进ACh、DA、5-HT等神经递质的分泌。此外，MDA 和 ROS 水平降低也支持氧化应激受到抑制。在炎症因子方面，SYN1过表达的AD大鼠中IL-6、IL-1β和TNF-α的水平显着降低。结论：SYN1过表达通过激活cAMP信号通路抑制氧化应激和炎症反应，从而改善AD大鼠的认知功能并促进多种神经递质的释放。这些发现可能为AD的靶向诊断和治疗提供理论依据。

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Synapsin 1 Ameliorates Cognitive Impairment and Neuroinflammation in Rats with Alzheimer’s Disease: An Experimental and Bioinformatics Study

Background::: Alzheimer’s disease (AD) is a persistent neuropathological injury that manifests via neuronal/synaptic death, age spot development, tau hyperphosphorylation, neuroinflammation, and apoptosis. Synapsin 1 (SYN1), a neuronal phosphoprotein, is believed to be responsible for the pathology of AD. Objective:: This study aimed to elucidate the exact role of SYN1 in ameliorating AD and its potential regulatory mechanisms. Methods:: The AD dataset GSE48350 was downloaded from the GEO database, and SYN1 was focused on differential expression analysis and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. After establishing an AD rat model, they were treated with RNAi lentivirus to trigger SYN1 overexpression. The amelioration of SYN1 in AD-associated behavior was validated using multiple experiments (water maze test and object recognition test). SYN1’s repairing effect on the important factors in AD was confirmed by detecting the concentration of inflammatory factors (interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α), neurotransmitters (acetylcholine (ACh), dopamine (DA), and 5-hydroxytryptophan (5-HT)) and markers of oxidative stress (glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS)). Molecular biology experiments (qRT-PCR and western blot) were performed to examine AD-related signaling pathways after SYN1 overexpression. Results:: Differential expression analysis yielded a total of 545 differentially expressed genes, of which four were upregulated and 541 were downregulated. The enriched pathways were basically focused on synaptic functions, and the analysis of the protein– protein interaction network focused on the key genes in SYN1. SYN1 significantly improved the spatial learning and memory abilities of AD rats. This enhancement was reflected in the reduced escape latency of the rats in the water maze, the significantly extended dwell time in the third quadrant, and the increased number of crossings. Furthermore, the results of the object recognition test revealed reduced time for rats to explore familiar and new objects. After SYN1 overexpression, the cAMP signaling pathway was activated, the phosphorylation levels of the CREB and PKA proteins were elevated, and the secretion of neurotransmitters such as ACh, DA, and 5-HT was promoted. Furthermore, oxidative stress was suppressed, as supported by decreased levels of MDA and ROS. Regarding inflammatory factors, the levels of IL-6, IL-1β, and TNF-α were significantly reduced in AD rats with SYN1 overexpression. Conclusion:: SYN1 overexpression improves cognitive function and promotes the release of various neurotransmitters in AD rats by inhibiting oxidative stress and inflammatory responses through cAMP signaling pathway activation. These findings may provide a theoretical basis for the targeted diagnosis and treatment of AD.

更新日期：2024-01-12

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