期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：37
DOI：10.1073/pnas.2201137119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Neuroinflammation, a major hallmark of Alzheimer’s disease (AD), has recently emerged as a potential therapeutic target. The important role of TNF-α, a master pro-inflammatory cytokine, in AD is well known. However, anti–TNF-α therapies have failed to treat AD, possibly due to the opposing functions of its receptors TNFR1 (neurodegeneration) and TNFR2 (neuroprotection). Thus, in this study, we investigated the effects of activating TNFR2 with a TNFR2 agonist in an AD mouse model. We show that stimulation of TNFR2 mitigates neuropathological features in AD mice by drastically decreasing the production rate of amyloid β and increasing its clearance by glial cells, resulting in an improvement of memory functions. Therefore, TNFR2 activation may be valuable as potential therapy for AD.
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.
关键词：enAlzheimer’s diseaseTNFneuroinflammationTNFR2 agonistJ20 mouse model
