Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
Department of Internal Medicine II, University of Würzburg, Würzburg, Germany.
J Alzheimers Dis. 2023;94(3):977-991. doi: 10.3233/JAD-221230.
Tumor necrosis factor-alpha (TNF-α) is a master cytokine involved in a variety of inflammatory and neurological diseases, including Alzheimer's disease (AD). Therapies that block TNF-α proved ineffective as therapeutic for neurodegenerative diseases, which might be explained by the opposing functions of the two receptors of TNF (TNFRs): while TNFR1 stimulation mediates inflammatory and apoptotic pathways, activation of TNFR2 is related to neuroprotection. Despite the success of targeting TNFR2 in a transgenic AD mouse model, research that better mimics the human context is lacking.
The aim of this study is to investigate whether stimulation of TNFR2 with a TNFR2 agonist is effective in activating human TNFR2 and attenuating AD neuropathology in the J20xhuTNFR2-k/i mouse model.
Transgenic amyloid-β (Aβ)-overexpressing mice containing a human extracellular TNFR2 domain (J20xhuTNFR2-k/i) were treated with a TNFR2 agonist (NewStar2). After treatment, different behavioral tests and immunohistochemical analysis were performed to assess different parameters, such as cognitive functions, plaque deposition, synaptic plasticity, or microglial phagocytosis.
Treatment with NewStar2 in J20xhuTNFR2-k/i mice resulted in a drastic decrease in plaque load and beta-secretase 1 (BACE-1) compared to controls. Moreover, TNFR2 stimulation increased microglial phagocytic activity, leading to enhanced Aβ clearance. Finally, activation of TNFR2 rescued cognitive impairments and improved synaptic plasticity.
Our findings demonstrate that activation of human TNFR2 ameliorates neuropathology and improves cognitive functions in an AD mouse model. Moreover, our study confirms that the J20xhuTNFR2-k/i mouse model is suitable for testing human TNFR2-specific compounds.
肿瘤坏死因子-α（TNF-α）是一种参与多种炎症和神经疾病的主要细胞因子，包括阿尔茨海默病（AD）。阻断 TNF-α 的治疗方法被证明对神经退行性疾病无效，这可能是由于 TNF 的两种受体（TNFRs）的功能相反：虽然 TNFR1 刺激介导炎症和凋亡途径，但 TNFR2 的激活与神经保护有关。尽管在转基因 AD 小鼠模型中靶向 TNFR2 取得了成功，但缺乏更能模拟人类情况的研究。
本研究旨在探讨 TNFR2 激动剂刺激 TNFR2 是否能有效激活人 TNFR2 并减轻 J20xhuTNFR2-k/i 小鼠模型中的 AD 神经病理学。
用 TNFR2 激动剂（NewStar2）处理含有人细胞外 TNFR2 结构域的转基因淀粉样蛋白-β（Aβ）过度表达小鼠（J20xhuTNFR2-k/i）。治疗后，进行不同的行为测试和免疫组织化学分析，以评估不同的参数，如认知功能、斑块沉积、突触可塑性或小胶质细胞吞噬作用。
与对照组相比，J20xhuTNFR2-k/i 小鼠中用 NewStar2 治疗导致斑块负荷和β-分泌酶 1（BACE-1）明显减少。此外，TNFR2 刺激增加了小胶质细胞的吞噬活性，导致 Aβ 清除增加。最后，激活 TNFR2 改善了认知障碍和改善了突触可塑性。
我们的研究结果表明，激活人 TNFR2 可改善 AD 小鼠模型中的神经病理学和认知功能。此外，我们的研究证实，J20xhuTNFR2-k/i 小鼠模型适合测试人 TNFR2 特异性化合物。
