ArticleJournal of Alzheimer's disease : JAD2023
Activation of TNF Receptor 2 Improves Synaptic Plasticity and Enhances Amyloid-β Clearance in an Alzheimer's Disease Mouse Model with Humanized TNF Receptor 2.
Article in Journal of Alzheimer's disease : JAD, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it, 17 citations in OpenAlex.
- The role of TNF signaling pathway in post-stroke cognitive impairment: a systematic review.Annals of medicine · 2025Pooled it
- BDNF Protects Against Neuronal Damage Induced by TNF and β-Amyloid Peptides by Targeting JNK Activation.Neurochemical research · 2026Article
- Unravelling Epigenetic Modulation via MicroRNA Delivery: A Therapeutic Frontier for Alzheimer's.Molecular neurobiology · 2026Review
- Association of soluble tumor necrosis factor receptor 1 with tau pathology, brain atrophy, and cognitive decline: a longitudinal study.BMC medicine · 2026Article
- Systemic inflammation as a central player in the initiation and development of Alzheimer's disease.Immunity & ageing : I & A · 2025Review
- TNFR2 Agonism: Basic Science and Promising Treatment for Multiple Sclerosis and Related Diseases.International journal of molecular sciences · 2025Review
- Sex-chromosome complement and Activin-A shape the therapeutic potential of TNFR2 activation in a model of MS and CNP.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Plasma Proteomic Biomarkers in Alzheimer's Disease and Cardiovascular Disease: A Longitudinal Study.International journal of molecular sciences · 2024Article
- Tumor necrosis factor receptor 2 activation elicits sex-specific effects on cortical myelin proteins and functional recovery in a model of multiple sclerosis.Brain research bulletin · 2024Article
- Generating Bone Marrow Chimeric Mouse Using GPR120 Deficient Mouse for the Study of DHA Inhibitory Effect on Osteoclast Formation and Bone Resorption.International journal of molecular sciences · 2023Article
- Higher p-Cresol sulfate and tumor necrosis factor (TNF)-α levels are associated with cognitive improvement through increased TNF receptor 2 in individuals with mild cognitive impairment: A cross-sectional mediation analysis.Journal of Alzheimer's disease reportsArticle
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTumor 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.
objectiveThe 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.
methodsTransgenic 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.
resultsTreatment 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.
conclusionOur 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.
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