Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation.

IF 1.7 Q4 NEUROSCIENCES
Neurology Research International Pub Date : 2025-01-30 eCollection Date: 2025-01-01 DOI:10.1155/nri/8948290
Shao Qin Tiong, Raxshanaa N Mohgan, Jia Yee Quek, Jennifer Yue Suan Liew, Grace Yee Seen Wong, Zi Qing Thang, Zhi Ling Chan, Sook Yee Gan, Elaine Wan Ling Chan
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引用次数: 0

Abstract

Background: Abnormal elevation of transforming growth factor-beta (TGF-β) has been observed among Alzheimer's disease (AD) patients. This may be due to microglia-mediated release of proinflammatory cytokines, which promote neuroinflammation and neuronal apoptosis. Silencing of TGFBR1, a gene encoding TGF-β receptor type I (TGF-βR1), has resulted in neuronal survival from amyloid-beta (Aβ)-induced neurotoxicity. Therefore, the present study investigated the neuroprotective effect of TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Methods: The neuroprotective effect of TGF-βR1 inhibitors against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation were investigated using the RealTime-Glo™ MT Cell Viability Assay. The inhibitory effect of TGF-βR1 inhibitors on Aβ-induced microglia-mediated production of proinflammatory cytokines (TNF-α and IL-1β) was determined using enzyme-linked immunosorbent assay (ELISA). Results: TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) at the tested concentrations (6.25-150 nM) showed no significant cytotoxicity effects on SH-SY5Y and BV-2 cells. Moreover, treatments with these inhibitors exhibited neuroprotection on SH-SY5Y cells against Aβ-induced direct neurotoxicity. The trend of cell viability after 24 h treatment also supports the microscopic images of the cells' morphology. Furthermore, pretreatment with these inhibitors conferred indirect neuroprotective effect against Aβ-induced microglia-mediated neuroinflammation by attenuating the production of proinflammatory cytokines (TNF-α and IL-1β). Conclusion: The inhibition of the TGF-β signaling pathway in neuronal and microglia cells by TGF-βR1 inhibitors resulted in neuroprotection against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Hence, targeting the TGF-β signaling pathway in both neuronal and microglia cells could provide a promising therapeutic strategy in AD.

抑制转化生长因子-β信号通路对β-淀粉样蛋白诱导的直接神经毒性和小胶质细胞介导的神经炎症具有神经保护作用
背景:在阿尔茨海默病(AD)患者中观察到转化生长因子-β (TGF-β)异常升高。这可能是由于小胶质细胞介导的促炎细胞因子的释放,促炎细胞因子促进神经炎症和神经元凋亡。TGFBR1是一种编码TGF-β受体I型(TGF-β r1)的基因,其沉默可导致β淀粉样蛋白(a β)诱导的神经毒性神经元存活。因此,本研究探讨了TGF-βR1抑制剂(RepSox, Galunisertib和Vactosertib)对a β诱导的直接神经毒性和小胶质细胞介导的神经炎症的神经保护作用。方法:采用RealTime-Glo™MT细胞活力测定法,研究TGF-βR1抑制剂对a β诱导的直接神经毒性和小胶质细胞介导的神经炎症的神经保护作用。采用酶联免疫吸附法(ELISA)检测TGF-βR1抑制剂对a β诱导的小胶质细胞介导的促炎细胞因子(TNF-α和IL-1β)产生的抑制作用。结果:TGF-βR1抑制剂(RepSox、Galunisertib、Vactosertib)在6.25 ~ 150 nM浓度下对SH-SY5Y和BV-2细胞无明显细胞毒性作用。此外,用这些抑制剂治疗SH-SY5Y细胞对a β诱导的直接神经毒性具有神经保护作用。处理24 h后细胞活力的变化趋势也支持了细胞形态的显微图像。此外,这些抑制剂预处理通过减少促炎细胞因子(TNF-α和IL-1β)的产生,对a β诱导的小胶质细胞介导的神经炎症具有间接的神经保护作用。结论:TGF-β r1抑制剂可抑制神经元和小胶质细胞中TGF-β信号通路,对a β诱导的直接神经毒性和小胶质细胞介导的神经炎症具有神经保护作用。因此,靶向神经元和小胶质细胞中的TGF-β信号通路可能是一种很有前景的治疗AD的策略。
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来源期刊
CiteScore
3.50
自引率
0.00%
发文量
10
审稿时长
17 weeks
期刊介绍: Neurology Research International is a peer-reviewed, Open Access journal that publishes original research articles, review articles, and clinical studies focusing on diseases of the nervous system, as well as normal neurological functioning. The journal will consider basic, translational, and clinical research, including animal models and clinical trials.
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