A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an Alzheimer's disease mouse model

Natalia Ortí-Casañ, Inge S Zuhorn, Petrus J W Naudé, Peter P De Deyn, Pauline E M van Schaik, Harald Wajant, Ulrich L M Eisel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)e2201137119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
Publication statusPublished - 13-Sept-2022


  • Alzheimer Disease/drug therapy
  • Amyloid beta-Peptides/genetics
  • Animals
  • Cognition/drug effects
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Neuroprotective Agents/pharmacology
  • Receptors, Tumor Necrosis Factor, Type II/agonists
  • Tumor Necrosis Factor-alpha/metabolism

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