Title | 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. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Ortí-Casañ, N, Wajant, H, H Kuiperij, B, Hooijsma, A, Tromp, L, Poortman, IL, Tadema, N, de Lange, JHE, Verbeek, MM, De Deyn, PP, Naudé, PJW, Eisel, ULM |
Journal | J Alzheimers Dis |
Volume | 94 |
Issue | 3 |
Pagination | 977-991 |
Date Published | 2023 |
ISSN | 1875-8908 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Animals, Humans, Mice, Mice, Transgenic, Neuronal Plasticity, Receptors, Tumor Necrosis Factor, Type II, Tumor Necrosis Factor-alpha |
Abstract | BACKGROUND: Tumor 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. 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-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. 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 Aβ 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. |
DOI | 10.3233/JAD-221230 |
Alternate Journal | J Alzheimers Dis |
PubMed ID | 37355890 |
PubMed Central ID | PMC10578215 |