NFPS 抑制 GlyT1 可促进淀粉样蛋白-β诱导的阿尔茨海默病动物模型的神经保护作用

IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemical Research Pub Date : 2024-06-18 DOI:10.1007/s11064-024-04190-0
Onésia Cristina Oliveira-Lima, Gustavo Almeida de Carvalho, Leandro do Prado Assunção, Alexandre Melo Bailão, Henning Ulrich, Bruno Lemes Marques, Antônio Carlos Pinheiro de Oliveira, Renato Santiago Gomez, Mauro Cunha Xavier Pinto
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引用次数: 0

摘要

阿尔茨海默病(AD)是一种神经退行性疾病,其特征是淀粉样蛋白-β的积累,导致N-甲基-D-天冬氨酸(NMDA)受体依赖性突触抑制、脊柱消失和记忆障碍。甘氨酸转运体1型(GlyT1)通过NMDA受体(NMDAR)调节谷氨酸能神经递质,为AD提供了一种潜在的替代治疗方法。本研究探讨了在淀粉样蛋白-β诱导的AD小鼠模型中抑制GlyT1的神经保护潜力。在海马内注射淀粉样蛋白-β前 24 小时,用 GlyT1 抑制剂 N-[3-([1,1-联苯]-4-氧基)-3-(4-氟苯基)丙基]-N-甲基甘氨酸(NFPS)处理 C57BL/6 小鼠。NFPS可预防淀粉样β诱导的短期和长期记忆认知缺陷,这一点在新物体识别和空间记忆任务中得到了证明。此外,NFPS预处理还能抑制淀粉样蛋白-β注射引起的小胶质细胞活化、星形胶质细胞反应和随后的神经元损伤。对接受NFPS治疗的小鼠海马进行了广泛的无标记UPLC-MSE定量蛋白质组学分析。在蛋白质组学中,KEGG富集分析表明多巴胺能突触、含嘌呤化合物生物合成过程和长期延时作用增加,葡萄糖分解过程和糖酵解过程途径减少。Western 印迹分析证实,NFPS 处理可提高 BDNF 水平,与 TRKB 磷酸化和 mTOR 激活增强相关。此外,NFPS 处理 6 h 后降低了 GluN2B 的表达,这与 CaMKIV 和 CREB 磷酸化的增加有关。总之,这些研究结果表明,NFPS对GlyT1的抑制激活了多种神经保护通路,增强了长期延时信号传导,对抗了淀粉样蛋白-β诱导的海马损伤。
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GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-β-Induced Alzheimer’s Disease Animal Model

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-β-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-β. NFPS pretreatment prevented amyloid-β-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-β injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-β-induced hippocampal damage.

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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