| First Author | Ortí-Casañ N | Year | 2023 |
| Journal | J Alzheimers Dis | Volume | 94 |
| Issue | 3 | Pages | 977-991 |
| PubMed ID | 37355890 | Mgi Jnum | J:351366 |
| Mgi Id | MGI:7663230 | Doi | 10.3233/JAD-221230 |
| Citation | Orti-Casan N, et al. (2023) Activation of TNF Receptor 2 Improves Synaptic Plasticity and Enhances Amyloid-beta Clearance in an Alzheimer's Disease Mouse Model with Humanized TNF Receptor 2. J Alzheimers Dis 94(3):977-991 |
| abstractText | BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a master cytokine involved in a variety of inflammatory and neurological diseases, including Alzheimer's disease (AD). Therapies that block TNF-alpha 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. OBJECTIVE: 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. METHODS: Transgenic amyloid-beta (Abeta)-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. RESULTS: 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 Abeta clearance. Finally, activation of TNFR2 rescued cognitive impairments and improved synaptic plasticity. CONCLUSION: 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. |
