PMID- 37355890
OWN - NLM
STAT- MEDLINE
DCOM- 20230808
LR  - 20231018
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Print)
IS  - 1387-2877 (Linking)
VI  - 94
IP  - 3
DP  - 2023
TI  - 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.
PG  - 977-991
LID - 10.3233/JAD-221230 [doi]
AB  - 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.
FAU - Orti-Casan, Natalia
AU  - Orti-Casan N
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen, The Netherlands.
FAU - Wajant, Harald
AU  - Wajant H
AD  - Department of Internal Medicine II, University of Wurzburg, Wurzburg, Germany.
FAU - Kuiperij, H Bea
AU  - Kuiperij HB
AD  - Department of Neurology, Radboud University Medical Center, Donders Institute for 
      Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Nijmegen, The 
      Netherlands.
FAU - Hooijsma, Annelien
AU  - Hooijsma A
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen, The Netherlands.
FAU - Tromp, Leon
AU  - Tromp L
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen, The Netherlands.
FAU - Poortman, Isabelle L
AU  - Poortman IL
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen, The Netherlands.
FAU - Tadema, Norick
AU  - Tadema N
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen, The Netherlands.
FAU - de Lange, Julia H E
AU  - de Lange JHE
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen, The Netherlands.
FAU - Verbeek, Marcel M
AU  - Verbeek MM
AD  - Department of Neurology, Radboud University Medical Center, Donders Institute for 
      Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Nijmegen, The 
      Netherlands.
AD  - Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, 
      The Netherlands.
FAU - De Deyn, Peter P
AU  - De Deyn PP
AD  - Department of Neurology and Alzheimer Center, University of Groningen, University 
      Medical Center Groningen, Groningen, The Netherlands.
FAU - Naude, Petrus J W
AU  - Naude PJW
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen, The Netherlands.
AD  - Department of Neurology and Alzheimer Center, University of Groningen, University 
      Medical Center Groningen, Groningen, The Netherlands.
FAU - Eisel, Ulrich L M
AU  - Eisel ULM
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Amyloid beta-Peptides)
SB  - IM
MH  - Mice
MH  - Humans
MH  - Animals
MH  - *Receptors, Tumor Necrosis Factor, Type II/genetics/metabolism/therapeutic use
MH  - *Alzheimer Disease/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Mice, Transgenic
MH  - Amyloid beta-Peptides/metabolism
MH  - Neuronal Plasticity
PMC - PMC10578215
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - TNF
OT  - TNFR2 agonist
OT  - humanized mouse model
OT  - neurodegeneration
OT  - neuroinflammation
COIS- The authors have no conflict of interest to report.
EDAT- 2023/06/25 06:42
MHDA- 2023/08/08 06:42
PMCR- 2023/10/16
CRDT- 2023/06/25 05:24
PHST- 2023/08/08 06:42 [medline]
PHST- 2023/06/25 06:42 [pubmed]
PHST- 2023/06/25 05:24 [entrez]
PHST- 2023/10/16 00:00 [pmc-release]
AID - JAD221230 [pii]
AID - 10.3233/JAD-221230 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2023;94(3):977-991. doi: 10.3233/JAD-221230.