Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen 9747 AG, Netherlands.
Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, Netherlands.
Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2201137119. doi: 10.1073/pnas.2201137119. Epub 2022 Aug 29.
Tumor necrosis factor-α (TNF-α) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer's disease (AD). Although the linkage between increased TNF-α levels and AD is widely recognized, TNF-α-neutralizing therapies have failed to treat AD. Previous research has associated this with the antithetic functions of the two TNF receptors, TNF receptor 1, associated with inflammation and apoptosis, and TNF receptor 2 (TNFR2), associated with neuroprotection. In our study, we investigated the effects of specifically stimulating TNFR2 with a TNFR2 agonist (NewStar2) in a transgenic Aβ-overexpressing mouse model of AD by administering NewStar2 in two different ways: centrally, via implantation of osmotic pumps, or systemically by intraperitoneal injections. We found that both centrally and systemically administered NewStar2 resulted in a drastic reduction in amyloid β deposition and β-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of Aβ. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates Aβ-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.
肿瘤坏死因子-α（TNF-α）是一种多功能的促炎细胞因子，与多种神经退行性疾病有关，包括阿尔茨海默病（AD）。尽管 TNF-α 水平升高与 AD 之间存在关联已被广泛认可，但 TNF-α 中和疗法未能治疗 AD。先前的研究将其与两种 TNF 受体的拮抗功能联系起来，TNF 受体 1 与炎症和细胞凋亡有关，而 TNF 受体 2（TNFR2）与神经保护有关。在我们的研究中，我们通过两种不同的方式使用 TNFR2 激动剂（NewStar2）来研究专门刺激 TNFR2 在 AD 转基因 Aβ 过表达小鼠模型中的作用：通过植入渗透泵进行中枢给药，或通过腹腔内注射进行全身给药。我们发现，中枢和全身给予 NewStar2 均可导致淀粉样蛋白β沉积和β-分泌酶 1 表达水平的急剧降低。此外，TNFR2 的激活增加了小胶质细胞和星形胶质细胞的激活，并促进了 Aβ 的摄取和降解。最后，NewStar2 治疗后认知功能也得到了改善。我们的结果表明，激活 TNFR2 可减轻 AD 小鼠模型中 Aβ 诱导的认知缺陷和神经病理学，并表明 TNFR2 刺激可能是 AD 的一种潜在治疗方法。
