PMID- 36037389
OWN - NLM
STAT- MEDLINE
DCOM- 20230824
LR  - 20230824
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 37
DP  - 2022 Sep 13
TI  - A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an 
      Alzheimer's disease mouse model.
PG  - e2201137119
LID - 10.1073/pnas.2201137119 [doi]
LID - e2201137119
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic, proinflammatory cytokine 
      related to different neurodegenerative diseases, including Alzheimer's disease 
      (AD). Although the linkage between increased TNF-alpha levels and AD is widely 
      recognized, TNF-alpha-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 Abeta-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 beta 
      deposition and beta-secretase 1 expression levels. Moreover, activation of TNFR2 
      increased microglial and astrocytic activation and promoted the uptake and 
      degradation of Abeta. Finally, cognitive functions were also improved after NewStar2 
      treatment. Our results demonstrate that activation of TNFR2 mitigates Abeta-induced 
      cognitive deficits and neuropathology in an AD mouse model and indicates that 
      TNFR2 stimulation might be a potential treatment for AD.
FAU - Orti-Casan, Natalia
AU  - Orti-Casan N
AUID- ORCID: 0000-0002-8103-7037
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen 9747 AG, Netherlands.
FAU - Zuhorn, Inge S
AU  - Zuhorn IS
AUID- ORCID: 0000-0002-7695-915X
AD  - Department of Biomedical Engineering, University of Groningen, University Medical 
      Center Groningen, Groningen 9713 AV, Netherlands.
FAU - Naude, Petrus J W
AU  - Naude PJW
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen 9747 AG, Netherlands.
AD  - Department of Neurology and Alzheimer Center, University of Groningen, University 
      Medical Center Groningen, Groningen 9713 AV, Netherlands.
FAU - De Deyn, Peter P
AU  - De Deyn PP
AUID- ORCID: 0000-0002-2228-2964
AD  - Department of Neurology and Alzheimer Center, University of Groningen, University 
      Medical Center Groningen, Groningen 9713 AV, Netherlands.
FAU - van Schaik, Pauline E M
AU  - van Schaik PEM
AUID- ORCID: 0000-0003-0343-4528
AD  - Department of Biomedical Sciences of Cells & Systems, Section Molecular 
      Neurobiology, University of Groningen, University Medical Center Groningen, 
      Groningen 9713 AV, Netherlands.
FAU - Wajant, Harald
AU  - Wajant H
AUID- ORCID: 0000-0002-2005-3949
AD  - Department of Internal Medicine II, University of Wurzburg, Wurzburg 97070, 
      Germany.
FAU - Eisel, Ulrich L M
AU  - Eisel ULM
AD  - Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life 
      Sciences, University of Groningen, Groningen 9747 AG, Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220829
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (NewSTAR2)
SB  - IM
CIN - Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2213903119. PMID: 36170251
MH  - Animals
MH  - Mice
MH  - *Alzheimer Disease/drug therapy/pathology
MH  - Amyloid beta-Peptides/genetics/metabolism
MH  - *Cognition/drug effects
MH  - Disease Models, Animal
MH  - Mice, Transgenic
MH  - Neuroprotective Agents/pharmacology/therapeutic use
MH  - *Receptors, Tumor Necrosis Factor, Type II/agonists
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC9482428
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - J20 mouse model
OT  - TNF
OT  - TNFR2 agonist
OT  - neuroinflammation
COIS- The authors declare no competing interest.
EDAT- 2022/08/30 06:00
MHDA- 2022/09/01 06:00
PMCR- 2022/08/29
CRDT- 2022/08/29 15:23
PHST- 2022/08/29 15:23 [entrez]
PHST- 2022/08/30 06:00 [pubmed]
PHST- 2022/09/01 06:00 [medline]
PHST- 2022/08/29 00:00 [pmc-release]
AID - 202201137 [pii]
AID - 10.1073/pnas.2201137119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2201137119. doi: 
      10.1073/pnas.2201137119. Epub 2022 Aug 29.