A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an Alzheimer's disease mouse model.
Alzheimer’s disease
J20 mouse model
TNF
TNFR2 agonist
neuroinflammation
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
13 09 2022
13 09 2022
Historique:
entrez:
29
8
2022
pubmed:
30
8
2022
medline:
1
9
2022
Statut:
ppublish
Résumé
Tumor necrosis factor-α (TNF-α) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer's disease (AD). Although the linkage between increased TNF-α levels and AD is widely recognized, TNF-α-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 Aβ-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 β deposition and β-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of Aβ. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates Aβ-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.
Identifiants
pubmed: 36037389
doi: 10.1073/pnas.2201137119
pmc: PMC9482428
doi:
Substances chimiques
Amyloid beta-Peptides
0
Neuroprotective Agents
0
Receptors, Tumor Necrosis Factor, Type II
0
Tumor Necrosis Factor-alpha
0
NewSTAR2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2201137119Commentaires et corrections
Type : CommentIn
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